The Beatson Institute Research Groups
The aim of our research is to understand the mechanisms that regulate cancer cell proliferation, survival and dissemination; to identify critical components of these pathways as targets for novel cancer therapies; and to help translate this knowledge to patient benefit. Our scientists are supported in this by having access to outstanding facilities and state-of-the-art services. In addition, the Institute has close ties to the University of Glasgow’s basic and clinical cancer research groups.
Click Research Groups in the right-hand menu to see what each group is working on.
Beatson publications are available as open access articles at Europe PubMed Central.
The aim of our research is to understand the mechanisms that regulate cancer cell proliferation, survival and dissemination; to identify critical components of these pathways as targets for novel cancer therapies; and to help translate this knowledge to patient benefit. Our scientists are supported in this by having access to outstanding facilities and state-of-the-art services. In addition, the Institute has close ties to the University of Glasgow's School of Cancer Sciences.
CRUK Scotland Institute publications are available as open access articles at Europe PubMed Central.
Research groups at the Scotland Institute are placing a particular emphasis on the following key themes:
- Cancer vulnerabilities caused by energetic stress and aberrant metabolism;
- Interplay between the tumour microenvironment, metastasis and recurrence; and
- Biology of early disease, aimed at developing a 'precision prevention' approach.
Prof Julia Cordero Profile
Introduction
The Le Quesne group combine classical molecular and quantitative microscopic imaging methods to ask questions about solid tumour biology. What can we directly observe in fully contextualised tumour tissue, the 'natural environment' of the malignant cell? How do malignant cells interact with the microenvironment of the tumour? What naturally selected strategies can we identify at cellular scale in human and mouse tumour tissues?
Our main interests lie in three areas:
- The dysregulation of mRNA translation in tumour cells and stroma, and how this reprogramming of the genome facilitates the malignant programme at the cellular level
- The refinement and development of highly multiplexed microscopic imaging methods to reveal additional levels of single-cellular detail in spatial context (e.g. quantity and subcellular localisation of multiple gene products at mRNA and protein levels)
- The improvement of biomarkers for the prediction of personalised treatment efficacy and patient prognostication.
We study common solid tumour types, but we have a particular emphasis on lung cancer and mesothelioma, and we have developed large focused collections of these tissues for study. In this area, we are engaged in study of how molecular and epigenetic events interact with tumour morphology in early stages of tumour development, and how morphology encodes specific survival strategies that drive tumour virulence and metastasis.
Lab Report
pdf Le Quesne Lab Report (1.53 MB)
Key Publications
AbdulJabbar K, Ahmed Raza SE, Rosenthal R, Jamal-Hanjani M, Veeriah S, Akarca A, Lund T, Moore DA, Salgado R, Al Bakir M, Zapata L, Hiley CT, Officer L, Sereno M, Smith CR, Loi S, Hackshaw A, Marafioti T, Quezada SA, Nicholas McGranahan N, Le Quesne J, TRACERx Consortium, Swanton C, Yuan Y. Geospatial Immune Variability Illuminates Differential Evolution of Lung Adenocarcinoma Nature Medicine. 2020; 26(7): 1054-62
Sereno M, Smith C, Baena J, He Z, Das M, Hastings R, Rake G, Fennell D, Nakas A, Moore D, Le Quesne J. Inclusion of multiple high-risk histopathological criteria improves the prediction of adjuvant chemotherapy efficacy in lung adenocarcinoma Journal of Pathology. 2020 Nov 6. Online ahead of print.
This study shows, using scanned images of >1000 archival tumour tissues with linked treatment and outcome data, that microscopic markers of tumour aggressiveness improve our prediction of which patients with lung cancer are likely to benefit from post-surgical chemotherapy, and also that we should offer this treatment more widely.
Waldron J, Tack D, Ritchey L, Wilczynska A, Turro E, Bevilacqua P, Assmann S, Bushell M, Le Quesne J. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity Genome Biology 2019 Dec 30;20(1):300
Here we show that eIF4A, an essential component of the protein synthesis machinery, is working by unwinding regions of mRNA very close to translation start sites, and not as generally assumed at the very 5’ end.
Moore D, Das M, Baena Acevedo J, Sinnadurai S, Sereno M, Smith C, McSweeney A, Su X, Officer L, Jones C, Dudek K, Guttery D, Spriggs R, Le Quesne J. In situ growth in early lung adenocarcinoma may represent precursor growth or invasive clone outgrowth - a clinically relevant distinction Modern Pathology 2019; 32: 1095-105
This was the first demonstration that the switch to invasiveness in lung cancer can reflect microenvironmental change/genomic plasticity in addition to genomic evolution.
Biography
Education and qualifications
2012: FRCPath
1999-2004: MBBS (Distinction in Medical Sciences), St. Bartholomew's and the Royal London School of Medicine
1996-1999: PhD, Department of Biochemistry, University of Leicester
1992-1995: MA Natural Sciences, Robinson College, University of Cambridge
Appointments
2020: Mazumdar-Shaw Professor of Molecular Pathology, University of Glasgow
2020: Assistant Professor (Hon), Leicester Cancer Research Centre, University of Leicester
2020: Visiting Associate Professor (Hon), University Hospitals of Leicester NHS Trust
2013-2020: Programme leader / Lead pathologist, MRC Toxicology Unit, University of Cambridge
2013-2020: Consultant Histopathologist (honorary), Glenfield Hospital, Leicester University Hospitals NHS Trust
2013-2020: Senior Lecturer, Leicester Cancer Research Centre, University of Leicester
2007-2013: CRUK Clinician Scientist Fellow, CRUK Cambridge Institute
2005-2007: Trainee general surgical pathologist, Department of Histopathology, Leicester Royal Infirmary
2004-2005: Pre-Registration House Officer, Leicester UHL NHS Trust
Current committee membership
CRUK PEACE governance Board
Board member, Journal of Pathology
Honours and awards
Associate fellowship, Higher Education Academy, 2018
Oakley Prize, Pathological Society, 2013
Foulkes Foundation Fellowship, 1999-2004
Recent Publications
2024
Pan X, AbdulJabbar K, Coelho-Lima J, Grapa AI, Zhang H, Cheung AHK, Baena J, Karasaki T, Wilson CR, Sereno M, Veeriah S, Aitken SJ, Hackshaw A, Nicholson AG, Jamal-Hanjani M, Swanton C, Yuan Y, Le Quesne J, Moore DA. The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma. Nat Cancer. 2024.
2023
Hatthakarnkul P, Ammar A, Pennel KAF, Officer-Jones L, Cusumano S, Quinn JA, Matly AAM, Alexander PG, Hay J, Andersen D, Lynch G, van Wyk HC, Maka N, McMillan DC, Le Quesne J, Thuwajit C, Edwards J. Protein expression of S100A2 reveals it association with patient prognosis and immune infiltration profile in colorectal cancer. J Cancer. 2023;14:1837-1847.
Hendrix E, Andrijes R, Boora U, Kaur A, Bundred JR, Officer-Jones L, pennie r, Powley I, Zayer A, Heilig R, Westrip CAE, Fletcher SF, Eaton CD, Kennedy TJ, Piasecka S, Fischer R, Smerdon SJ, Quesne JL, Coleman ML. A protein hydroxylase couples epithelial membrane biology to nucleolar ribosome biogenesis. bioRxiv. 2023;Volume:2023.2003.2015.532818.
Farahmand P, Gyuraszova K, Rooney C, Raffo-Iraolagoitia XL, Jayasekera G, Hedley A, Johnson E, Chernova T, Malviya G, Hall H, Monteverde T, Blyth K, Duffin R, Carlin LM, Lewis D, Le Quesne J, MacFarlane M, Murphy DJ. Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma. Frontiers in Toxicology. 2023;5.
Frankell AM, Dietzen M, Al Bakir M, Lim EL, Karasaki T, Ward S, Veeriah S, Colliver E, Huebner A, Bunkum A, Hill MS, Grigoriadis K, Moore DA, Black JRM, Liu WK, Thol K, Pich O, Watkins TBK, Naceur-Lombardelli C, Cook DE, Salgado R, Wilson GA, Bailey C, Angelova M, Bentham R, Martínez-Ruiz C, Abbosh C, Nicholson AG, Le Quesne J, Biswas D, Rosenthal R, Puttick C, Hessey S, Lee C, Prymas P, Toncheva A, Smith J, Xing W, Nicod J, Price G, Kerr KM, Naidu B, Middleton G, Blyth KG, Fennell DA, Forster MD, Lee SM, Falzon M, Hewish M, Shackcloth MJ, Lim E, Benafif S, Russell P, Boleti E, Krebs MG, Lester JF, Papadatos-Pastos D, Ahmad T, Thakrar RM, Lawrence D, Navani N, Janes SM, Dive C, Blackhall FH, Summers Y, Cave J, Marafioti T, Herrero J, Quezada SA, Peggs KS, Schwarz RF, Van Loo P, Miedema DM, Birkbak NJ, Hiley CT, Hackshaw A, Zaccaria S, Jamal-Hanjani M, McGranahan N, Swanton C. The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature. 2023; 616: 525–533
Karasaki T, Moore DA, Veeriah S, Naceur-Lombardelli C, Toncheva A, Magno N, Ward S, Bakir MA, Watkins TBK, Grigoriadis K, Huebner A, Hill MS, Frankell AM, Abbosh C, Puttick C, Zhai H, Gimeno-Valiente F, Saghafinia S, Kanu N, Dietzen M, Pich O, Lim EL, Martínez-Ruiz C, Black JRM, Biswas D, Campbell BB, Lee C, Colliver E, Enfield KSS, Hessey S, Hiley CT, Zaccaria S, Litchfield K, Birkbak NJ, Cadieux EL, Demeulemeester J, Van Loo P, Adusumilli PS, Tan KS, Cheema W, Sanchez-Vega F, Jones DR, Rekhtman N, Travis WD, Hackshaw A, Marafioti T, Salgado R, Le Quesne J, Nicholson AG, McGranahan N, Swanton C, Jamal-Hanjani M. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx. Nat Med. 2023; 29: 833–845
Laing S, Kruspig B, Shaw R, Officer-Jones L, Edwards S, McKinven D, Hsieh Y-C, Powley I, Brady N, Pennie R, Kwan R, Lima A, Myrta S, Periyasamy M, Dye IC, Nixon C, Clark G, Junttila MR, Maddalo D, Miller C, Ali S, Fuchter MJ, Nickles D, Kirschner K, Brown RB, Quesne JL, Strathdee D, Coffelt SB, Roberts E, Murphy DJ. ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma. bioRxiv. 2023:2023.2007.2024.550274.
May S, Müller M, Livingstone CR, Skalka GL, Walsh PJ, Nixon C, Hedley A, Shaw R, Clark W, Voorde JV, Officer-Jones L, Ballantyne F, Powley IR, Drake TM, Kiourtis C, Keith A, Rocha AS, Tardito S, Sumpton D, Le Quesne J, Bushell M, Sansom OJ, Bird TG. Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration. J Hepatol. 2023; 78: 1028-1036
Moore M, Pardo L, Mitchell L, Schmidt T, May S, Mueller M, Strathdee D, Bryson S, Hodge K, Lilla S, Zanivan S, Waldron J, McGarry L, Peter-Durairaj R, Kanellos G, Nixon C, Ballantyne F, LeQuesne J, Sansom OJ, Bird T, Bushell M, Norman JC. The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation. bioRxiv. 2023;Volume:2023.2008.2016.553544.
Román-Fernández A, Mansour MA, Kugeratski FG, Anand J, Sandilands E, Galbraith L, Rakovic K, Freckmann EC, Cumming EM, Park J, Nikolatou K, Lilla S, Shaw R, Strachan D, Mason S, Patel R, McGarry L, Katoch A, Campbell KJ, Nixon C, Miller CJ, Leung HY, Le Quesne J, Norman JC, Zanivan S, Blyth K, Bryant DM. Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Sci Adv. 2023;9:eabq1858.
Schmidt T, Dabrowska A, Waldron JA, Hodge K, Koulouras G, Gabrielsen M, Munro J, Tack DC, Harris G, McGhee E, Scott D, Carlin Leo M, Huang D, Le Quesne J, Zanivan S, Wilczynska A, Bushell M. eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation. Nucleic Acids Research. 2023; 51: 1859–1879
Thunnissen E, Beasley MB, Borczuk A, Dacic S, Kerr KM, Lissenberg-Witte B, Minami Y, Nicholson AG, Noguchi M, Sholl L, Tsao MS, Le Quesne J, Roden AC, Chung JH, Yoshida A, Moreira AL, Lantuejoul S, Pelosi G, Poleri C, Hwang D, Jain D, Travis WD, Brambilla E, Chen G, Botling J, Bubendorf L, Mino-Kenudson M, Motoi N, Chou TY, Papotti M, Yatabe Y, Cooper W. Defining Morphologic Features of Invasion in Pulmonary Nonmucinous Adenocarcinoma With Lepidic Growth: A Proposal by the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2023;18:447-462.
Waldron JA, Kanellos G, Smith RCL, Knight JRP, Munro J, Alexandrou C, Vlahov N, Pardo-Fernandez L, Moore M, Gillen SL, Strathdee D, Stevenson D, Warrander FC, Gilroy K, Nixon C, Cadden B, Powley I, Officer-Jones L, Ballantyne F, Hay J, Pennel K, Edwards J, Campbell AD, Ridgway RA, Coffelt SB, Norman J, Quesne JL, Bushell M, Sansom OJ. eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers. bioRxiv. 2023:2023.2011.2010.566546.
Zhang H, AbdulJabbar K, Moore DA, Akarca A, Enfield K, Jamal-Hanjani M, Raza SEA, Veeriah S, Salgado R, McGranahan N, Le Quesne J, Swanton C, Marafioti T, Yuan Y. Spatial positioning of immune hotspots reflects the interplay between B and T cells in lung squamous cell carcinoma. Cancer Res. 2023; 83:1410–1425.
Zhang H, AbdulJabbar K, Grunewald T, Akarca AU, Hagos Y, Sobhani F, Lecat CSY, Patel D, Lee L, Rodriguez-Justo M, Yong K, Ledermann JA, Le Quesne J, Hwang ES, Marafioti T, Yuan Y. Self-supervised deep learning for highly efficient spatial immunophenotyping. EBioMedicine. 2023;95:104769.
2022
Kamata T, Al Dujaily E, Alhamad S, So TY, Margaritaki O, Giblett S, Pringle JH, Le Quesne J, Pritchard C. Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment. Dis Model Mech. 2022;15:dmm049148
2021
Ghaddar N, Wang S, Woodvine B, Krishnamoorthy J, van Hoef V, Darini C, Kazimierczak U, Ah-Son N, Popper H, Johnson M, Officer L, Teodósio A, Broggini M, Mann KK, Hatzoglou M, Topisirovic I, Larsson O, Le Quesne J, Koromilas AE. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Nat Commun. 2021;12(1):4651.
Grosso S, Marini A, Gyuraszova K, Voorde JV, Sfakianos A, Garland GD, Tenor AR, Mordue R, Chernova T, Morone N, Sereno M, Smith CP, Officer L, Farahmand P, Rooney C, Sumpton D, Das M, Teodósio A, Ficken C, Martin MG, Spriggs RV, Sun XM, Bushell M, Sansom OJ, Murphy D, MacFarlane M, Le Quesne JPC, Willis AE. The pathogenesis of mesothelioma is driven by a dysregulated translatome. Nat Commun. 2021;12:4920.
Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, Gay DM, May-Wilson S, Smith EM, Najumudeen AK, Gilroy K, Ridgway RA, Flanagan DJ, Smith RCL, McDonald L, MacKay C, Cheasty A, McArthur K, Stanway E, Leach JD, Jackstadt R, Waldron JA, Campbell AD, Vlachogiannis G, Valeri N, Haigis KM, Sonenberg N, Proud CG, Jones NP, Swarbrick ME, McKinnon HJ, Faller WJ, Le Quesne J, Edwards J, Willis AE, Bushell M, Sansom OJ. MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer Discov. 2021;11(5):1228-1247.
Ntala C, Salji M, Salmond J, Officer L, Teodosio AV, Blomme A, McGhee EJ, Powley I, Ahmad I, Kruithof-de Julio M, Thalmann G, Roberts E, Goodyear CS, Jamaspishvili T, Berman DM, Carlin LM, Le Quesne J, Leung HY. Analysis of Prostate Cancer Tumor Microenvironment Identifies Reduced Stromal CD4 Effector T-cell Infiltration in Tumors with Pelvic Nodal Metastasis. Eur Urol Open Sci. 2021;29:19-29.
Phatak V, von Grabowiecki Y, Janus J, Officer L, Behan C, Aschauer L, Pinon L, Mackay H, Zanivan S, Norman JC, Kelly M, Le Quesne J, Muller PAJ. Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane. Cell Death Dis. 2021;12(2):207.
2020
AbdulJabbar K, Ahmed Raza SE, Rosenthal R, Jamal-Hanjani M, Veeriah S, Akarca A, Lund T, Moore DA, Salgado R, Al Bakir M, Zapata L, Hiley CT, Officer L, Sereno M, Smith CR, Loi S, Hackshaw A, Marafioti T, Quezada SA, Nicholas McGranahan N, Le Quesne J, TRACERx Consortium, Swanton C, Yuan Y. Geospatial Immune Variability Illuminates Differential Evolution of Lung Adenocarcinoma Nature Medicine. 2020; 26(7): 1054-62
Curtin N, Bányai K, Thaventhiran J, Le Quesne J, Helyes Z, Bai P. Repositioning PARP inhibitors for SARS-CoV-2 infection (COVID-19); a new multi-pronged therapy for ARDS? Br J Pharmacol. 2020; 177(16): 3635-45
Officer LK, Andreou KE, Teodósio AV, He Z, Le Quesne JP. Automated Co-in Situ Hybridization and Immunofluorescence Using Archival Tumor Tissue Methods Mol Biol 2020; 2148: 245-56
Sereno M, Smith C, Baena J, He Z, Das M, Hastings R, Rake G, Fennell D, Nakas A, Moore D, Le Quesne J. Inclusion of multiple high-risk histopathological criteria improves the prediction of adjuvant chemotherapy efficacy in lung adenocarcinoma Journal of Pathology, 2020; 78: 838-848
Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL, Jordan S, Lim E, Lang-Lazdunski L, Begum S, Dusmet M, Anikin V, Beddow E, Finch J, Asadi N, Popat S, Le Quesne J, Husain AN, Cookson WO, Moffatt MF, Nicholson AG. Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade Histopathology 2020; 77(3): 423-36
2019
Rakhit C, Trigg RM, Le Quesne J, Kelly M, Shaw JA, Pritchard C, Martins LM. Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA Dis Model Mech, 2019 Feb 12;12(2):dmm036863
Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanić M, Reading JL, Joshi K, Henry JY, Ghorani E, Wilson GA, Birkbak NJ, Jamal-Hanjani M, Veeriah S, Szallasi Z, Loi S, Hellmann MD, Feber A, Chain B, Herrero J, Quezada SA, Demeulemeester J, Van Loo P, Beck S, McGranahan N, Swanton C; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution Nature 2019; 567: 479-85.
This landmark study of the primary tumour tissues from the TraceRx cohort shows how tumours evolve under natural selection to evade the human immune system.
Moore D, Das M, Baena Acevedo J, Sinnadurai S, Sereno M, Smith C, McSweeney A, Su X, Officer L, Jones C, Dudek K, Guttery D, Spriggs R, Le Quesne J. In situ growth in early lung adenocarcinoma may represent precursor growth or invasive clone outgrowth - a clinically relevant distinction Modern Pathology 2019; 32: 1095-105
Fercoq F, Remion E, Frohberger SJ, Vallarino-Lhermitte N, Hoerauf A, Le Quesne J, Landmann F, Hübner MP, Carlin LM, Martin C. IL-4 receptor dependent expansion of lung CD169+ macrophages in microfilaria-driven inflammation PLoS Negl Trop Dis. 2019; 13(8): e7691
Officer LK, Andreou KE, Teodósio AV, He Z, Le Quesne J. Automated co-in situ hybridization and immunofluorescence using archival tumour tissue Methods Mol Biol. 2020; 2148: 245-56
Wilczynska A, Gillen S, Schmidt T, Meijer H, Jukes-Jones R, Langlais C, Kopra K, Lu W-T, Godfrey J, Hawley B, Hodge K, Zanivan S, Cain K, Le Quesne J, Bushell M. eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR Genome Biology 2019 Dec 2;20(1):262
Waldron J, Tack D, Ritchey L, Wilczynska A, Turro E, Bevilacqua P, Assmann S, Bushell M, Le Quesne J. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity Genome Biology 2019 Dec 30;20(1):300
Al-Dujaily E, Baena J, Das M, Sereno M, Smith C, Kamata T, Officer L, Pritchard C, Le Quesne J. Reduced pro-tumourigenic tumour-associated macrophages with statin use in premalignant human lung adenocarcinoma JNCI Cancer Spectrum 2019 Dec 13;4(2):pkz101
2018
Kolluri KK, Alifrangis C, Kumar N, Ishii Y, Price S, Michaut M, Williams S, Barthorpe S, Lightfoot H, Busacca S,Sharkey A, Yuan Z, Sage EK, Vallath S, Le Quesne J, Tice DA, Alrifai D, von Karstedt S, Montinaro A, Guppy N, Waller DA, Nakas A, Good R, Holmes A, Walczak H, Fennell DA, et al. Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells eLife 2018 Jan 18;7:e30224
Waldron J, Raza F, Le Quesne J. eIF4A alleviates the translational repression mediated by classical secondary structures more than by G-quadruplexes Nucleic Acids Research 2018 Apr 6;46(6):3075-87
Mackay H, Moore D, Hall C, Birkbak N, Jamal-Hanjani M, Karim S, Pathak V, Pinon L, MortonJ, Swanton C, Muller P, Le Quesne J. Genomic instability in mutant p53 cancer cells upon entotic engulfment Nature Communications 2018 Aug 3;9(1):3070
Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B; TRACERx Melanoma; TRACERx Renal; TRACERx Lung consortia, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies Cancer Cell 2018 Apr 9;33(4):649-663.e4
Lazarus KA, Hadi F, Zambon E, Bach K, Santolla M-F, Watson JK, Correia LL, Das M, Ugur R, Pensa S, Becker L, Campos LS, Ladds G, Pentao L, Evan G, McCaughan F, Le Quesne J, Lee J-H, Calado D, Khaled WT. BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma Nature Communications 2018 Aug 20;9(1):3327
Kruspig B, Monteverde T, Neidler S, Hock A, Kerr E, Nixon C, Clark W, Hedley A, Laing S, Coffelt SB, Le Quesne J, Dick C, Vousden K, Martins CP, Murphy DJ. The ERBB network facilitates KRAS-driven lung tumorigenesis Science Translational Medicine 2018 Jun 20;10(446):eaao2565
Amelio I, Mancini M, Petrova V, Cairns RA, Vikhreva P, Nicolai S, Marini A, Antonov AA, Le Quesne J, Baena Acevedo JD, Dudek K, Sozzi G, Pastorino U, Knight RA, Mak TW, Melino G. p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression Proc Natl Acad Sci USA 2018 Nov 13;115(46):E10869-E10878
2017
Karekla E, 6. Liao WJ, Sharp B, Pugh J, Reid H, Le Quesne JP, Moore D, Pritchard CA, MacFarlane M, Pringle JH. Ex vivo explant cultures of non-small cell lung carcinoma enable evaluation of primary tumor responses to anticancer therapy Cancer Research 2017; 77:2029-2039
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, et al. Tracking the Evolution of Non-Small-Cell Lung Cancer New Engl J Med. 2017 Jun 1;376(22):2109-2121
Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution Nature 2017 Apr 26;545(7655):446-451
Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Miranda Rota E, Dahan R, Georgiou A, et al. Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors Immunity 2017 Apr 18;46(4):577-86
Chernova T, Murphy F, Galavotti S, Sux X, Powley IR, Grosso S, Schinwald A, Zacarias-Cabeza J, Dudek K, Dinsdale D, Le Quesne J, Bennet J, Nakas A, Greaves P, Poland CA, Donaldson K, Bushell M, Willis AE, MacFarlane M. Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf) Current Biology 2017 Nov 6;27(21):3302-14.e6
McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, Birkbak NJ, Veeriah S, Van Loo P, Herrero J, Swanton C; TRACERx Consortium. Allele-specific HLA loss and immune escape in lung cancer evolution Cell 2017 Nov 30;171(6):1259-1271.e11
2016
Hiley CT, Le Quesne J, Santis G, Sharpe R, de Castro DG, Middleton G, Swanton C. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease The Lancet 2016 Sep 3;388(10048):1002-11
Blows FM, Ali HR, Dawson SJ, Le Quesne J, Provenzano E, Caldas C, Pharoah PD. Decline in Antigenicity of Tumor Markers by Storage Time Using Pathology Sections Cut From Tissue Microarrays Appl Immunohistochem Mol Morphol. 2016 Mar;24(3):221-6
Busacca S, Law EW, Powley IR, Proia DA, Sequeira M, Le Quesne J, Klabatsa A, Edwards JM, Matchett KB, Luo JL, Pringle JH, El-Tanani M, MacFarlane M, Fennell DA. Resistance to HSP90 inhibition involving loss of MCL1 addiction Oncogene 2016 Mar 24;35(12):1483-92
Lab Members
Associate Scientist
Ian Powley
Postdoctoral Scientist
Nicolas Poulain
Histopathology Technology Manager
Leah Officer-Jones
Senior Scientific Officers
Silvia Cusumano
Catherine Ficken
Scientific Officers
Fiona Ballantyne
Rachel Pennie
Clinical Research Fellow
Kai Rakovic
Honorary Clinical Fellow
Alexandra McLaren
PhD student
Farzaneh Seyedshahi
Introduction
The adult intestine is a major barrier epithelium with vital endocrine, immune and metabolic roles, leading to the coordination of whole-body physiology. These functions are achieved by specialised cells such as absorptive enterocytes and secretory enteroendocrine cells, which are generated by intestinal stem cells (ISCs). Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How do these signals integrate to preserve intestinal and whole-body health?
Work in our laboratory is devoted to deciphering the cellular and molecular mechanisms regulating ISC behaviour during tissue regeneration and tumourigenesis. We are also interested in understanding how the intestine interacts with other tissues and organs to maintain organismal balance and how these interactions are deregulated in intestinal diseases such as cancer or inflammation. We use the fruit fly Drosophila melanogaster as our primary in vivo research model system combined with suitable mammalian paradigms.
Our research aims to identify mechanisms that could be used in translational efforts to restore intestinal regeneration as well as to prevent malignant transformation of the intestine and alleviate the systemic consequences of intestinal malfunction.
Biography
Education and qualifications
2007. Ph.D. degree in the Molecular Cell Biology Program, Washington University School of Medicine. Saint Louis, MO, USA. Thesis Advisor: Dr. Ross L. Cagan
1999: “Licenciada en Biología Molecular”, San Luis National University. San Luis, Argentina.
Appointments
2016-present: Senior Research Fellow, School of Cancer Sciences, University of Glasgow.
2016-present: Honorary Group Leader, Cancer Research UK Scotland Institute, Glasgow.
2016-Present: Senior Research Fellow. Wolfson Wohl Cancer Research Centre. Institute of Cancer Sciences, University of Glasgow.
2014-2016. Junior Research Fellow. Wolfson Wohl Cancer Research Centre. Institute of
Cancer Sciences. University of Glasgow. Glasgow, United Kingdom.
2009-2014: Postdoctoral Fellow, Cancer Research UK Beatson Institute
2007-2008: Post-doctoral Fellow, Mount Sinai School of Medicine New York, NY. USA
2000-2002: Research Assistant, Department of Internal Medicine, Renal Division, Washington University School of Medicine, Saint Louis, MO, USA
Recent Publications
2022
Chen Z, Cordero J, Alqarni AM, Slack C, Zeidler MP, Bellantuono I. Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner. J Gerontol A Biol Sci Med Sci. 2022;77:1494-1502.
Medina A, Bellec K, Polcowñuk S, Cordero JB. Investigating local and systemic intestinal signalling in health and disease with Drosophila. Dis Model Mech. 2022; 15:dmm049332
2021
Guillermin O, Angelis N, Sidor CM, Ridgway R, Baulies A, Kucharska A, Antas P, Rose MR, Cordero J, Sansom O, Li VSW, Thompson BJ. Wnt and Src signals converge on YAP-TEAD to drive intestinal regeneration. Embo j. 2021:e105770.
Hodgson JA, Parvy JP, Yu Y, Vidal M, Cordero JB. Drosophila Larval Models of Invasive Tumorigenesis for In Vivo Studies on Tumour/Peripheral Host Tissue Interactions during Cancer Cachexia. Int J Mol Sci. 2021;22: 8317
Nászai M, Bellec K, Yu Y, Román-Fernández A, Sandilands E, Johansson J, Campbell AD, Norman JC, Sansom OJ, Bryant DM, Cordero JB. RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis. Elife. 2021 Jun 7;10:e63807.
Perochon J, Yu Y, Aughey GN, Medina AB, Southall TD, Cordero JB. Dynamic adult tracheal plasticity drives stem cell adaptation to changes in intestinal homeostasis in Drosophila. Nat Cell Biol. 2021; 23:485–496
2020
Bellec K, Cordero JB. The Peroxisome: A New Player in Intestinal Epithelial Repair. Dev Cell. 2020;53:131-132.
2019
Johansson J, Naszai M, Hodder M, Pickering K, Miller BW, Ridgway RA, Yu Y, Peschard P, Brachmann B, Campbell AD, Cordero, JB1, Sansom, OJ. RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes. Cell Stem Cell. Apr 4;24(4):592-607.e7. Commentary in Cell Stem Cell 2019 Apr 4;24:499-500.
Parvy JP1, Yu Y, Dostalova A, Kondo S, Kurjan A, Bulet P, Lemaitre B, Vidal M, Cordero JB. The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila. Elife. 2019;8: e45061. Recommended by the Faculty of 1000.
Scopelliti A, Bauer C, Yu Y, Zhang T, Krüspig B, Murphy DJ, Vidal M, Maddocks OK, Cordero JB. A neuronal relay mediates a nutrient responsive gut/fat body axis regulating energy homeostasis in adult Drosophila. Cell Metab. 2019 Feb 5;29:269-284.e10.
2018
Parvy JP, Hodgson JA, Cordero JB. Drosophila as a Model System to Study Nonautonomous Mechanisms Affecting Tumour Growth and Cell Death. Biomed Res Int. 2018:7152962.
Perochon J, Carroll LR, Cordero JB. Wnt Signalling in Intestinal Stem Cells: Lessons from Mice and Flies. Genes (Basel). 2018;9. pii: E138.
2017
Tian A, Benchabane H, Wang Z, Zimmerman C, Xin N, Perochon J, Kalna G, Sansom OJ, Cheng C, Cordero JB, Ahmed Y. Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing. PLoS Genet. 2017 Jul 14;13:e1006870.
2016
Scopelliti A, Bauer C, Cordero J and Vidal M. Bursicon-α subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-β. Cell Cycle. 2016;15:1538-44.
Elbediwy A, Vincent-Mistiaen ZI, Spencer-Dene B, Stone RK, Boeing S, Wculek SK, Cordero J, Tan EH, Ridgway R, Brunton VG, Sahai E, Gerhardt H, Behrens A, Malanchi I, Sansom OJ, Thompson BJ. Integrin signalling regulates YAP and TAZ to control skin homeostasis. Development. 2016;143:1674-87.
Introduction
Research Fellow, Senior Clinical Lecturer in Colorectal Surgery
Honorary Consultant Surgeon, Glasgow Royal Infirmary
Colorectal cancer patients die as a result of metastatic progression or disease recurrence following surgery. Though surgery can cure some patients of colorectal cancer with liver limited disease, the vast majority cannot be treated effectively. Current systemic therapies offer modest survival benefits. Understanding the mechanisms of metastatic progression in the most aggressive forms of colorectal cancer will permit therapeutic targeting in the future alongside surgery to improve outcomes for my patients.
My current research interests focus on the immune microenvironment of locally advanced and metastatic colorectal cancer. We have identified the importance of common white blood cells – neutrophils – in driving metastatic progression in models of cancer. Using state-of-the-art in vivo models and human specimens, I am currently seeking to understand the interactions between neutrophil populations, other immune cells and tumour cells in driving progression of colorectal cancer. This work will help to identify vulnerabilities in the immune system that may be harnessed with immunotherapies to target more aggressive colorectal cancer. My clinical work at Glasgow Royal Infirmary operating on patients with locally advanced rectal cancer provides an opportunity to interact with this patient group, obtain relevant clinical samples and help prioritise my research.
Other funding:
Biography
Education and qualifications
2019: Intercollegiate FRCS.
2015: PhD: Investigating the role of CXCR2 signalling in pancreatic inflammation and cancer. College of Medical, Veterinary and Life Sciences. University of Glasgow. Supervisor: Professor Owen Sansom.
2009: Intercollegiate MRCS (RCPSG)
2004: BSc Med Sci, Clinical Medicine, University of Glasgow. Supervisor: Dr Ann-Marie McNicol
1996: MBChB,University of Glasgow.
Appointments
2017-present: NES/CSO Clinical Lectureship
2011–2014: Wellcome Trust Clinical Research Fellow
2010–2011: Lister Fellow Glasgow Royal Infirmary August
Recent Publications
2024
Fetit R, McLaren A, White M, Mills ML, Falconer J, Cortes-Lavaud X, Gilroy K, Lannagan TR, Ridgway RA, Nixon C, Naiker V, Njunge R, Clarke CJ, Whyte D, Kirschner K, Jackstadt R, Norman JC, Carlin LM, Campbell AD, Sansom OJ, Steele CW. Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Res Commun. 2024.
Pennel KAF, Hatthakarnkul P, Wood CS, Lian GY, Al-Badran SSF, Quinn JA, Legrini A, Inthagard J, Alexander PG, van Wyk H, Kurniawan A, Hashmi U, Gillespie MA, Mills M, Ammar A, Hay J, Andersen D, Nixon C, Rebus S, Chang DK, Kelly C, Harkin A, Graham J, Church D, Tomlinson I, Saunders M, Iveson T, Lannagan TRM, Jackstadt R, Maka N, Horgan PG, Roxburgh CSD, Sansom OJ, McMillan DC, Steele CW, Jamieson NB, Park JH, Roseweir AK, Edwards J. JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. J Exp Clin Cancer Res. 2024;43(1):64.
2023
Fetit R, White M, Mills ML, Cortes-Lavaud X, McLaren A, Falconer J, Gilroy K, Nixon C, Kirschner K, Jackstadt R, Campbell AD, Sansom OJ, Steele CW. Characterising neutrophil subtypes in cancer using human and murine single-cell RNA sequencing datasets. bioRxiv. 2023;Volume:2023.2007.2013.548820.
McLaren AS, Fetit R, Wood CS, Falconer J, Steele CW. Single cell sequencing of neutrophils demonstrates phenotypic heterogeneity and functional plasticity in health, disease, and cancer. Chin Clin Oncol. 2023;10.21037/cco-22-121.
McMahon RK, O'Cathail SM, Nair H, Steele CW, Platt JJ, Digby M, McDonald AC, Horgan PG, Roxburgh CSD. The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer. Colorectal Dis. 2023;10.1111/codi.16667.
Wood CS, Pennel KAF, Leslie H, Legrini A, Cameron AJ, Melissourgou-Syka L, Quinn JA, van Wyk HC, Hay J, Roseweir AK, Nixon C, Roxburgh CSD, McMillan DC, Biankin AV, Sansom OJ, Horgan PG, Edwards J, Steele CW, Jamieson NB. Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases. Cancer Res. 2023;83:1329-1344.
2022
Pennel KA, Quinn JA, Nixon C, Inthagard J, van Wyk HC, Chang D, Rebus S, Hay J, Maka NN, Roxburgh CS, Horgan PG, McMillan DC, Park JH, Roseweir AK, Steele CW, Edwards J. CXCL8 expression is associated with advanced stage, right sidedness, and distinct histological features of colorectal cancer. J Pathol Clin Res. 2022;8:509-520
Persson P, Chong P, Steele CW, Quinn M. Prevention and management of complications in pelvic exenteration. Eur J Surg Oncol. 2022; 48:2277-2283.
Gould LE, Pring ET, Drami I, Moorghen M, Naghibi M, Jenkins JT, Steele CW, Roxburgh CS. A systematic review of the pathological determinants of outcome following resection by pelvic exenteration of locally advanced and locally recurrent rectal cancer. Int J Surg. 2022;104:106738.
2021
Han J, Tao M, Wu X, Li D, Ma Y, Dawood S, Steele CW, Tan KK, Wang Q. Reporting quality of practice guidelines on colorectal cancer: evaluation using the RIGHT reporting checklist. Ann Transl Med. 2021;9(14):1175.
Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021.
Galbraith NJ, Wood C, Steele CW. Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies. Cancers (Basel). 2021;13(14).
Gillespie MA, Steele CW, Lannagan TRM, Sansom OJ, Roxburgh CSD. Pre-clinical modelling of rectal cancer to develop novel radiotherapy-based treatment strategies. Oncol Rev. 2021;15:511.
McSorley ST, Steele CW, Anderson JH, McKinlay S. Comment on 'Preoperative intravenous iron therapy and survival after colorectal cancer surgery: long-term results from the IVICA randomized controlled trial'. Colorectal Dis. 2021;23(2):555-556.
2020
Bisset CN, Carter B, Law J, Hewitt J, Parmar K, Moug SJ; ELF Study Group Collaborative Authorship. The influence of social media on recruitment to surgical trials. BMC Med Res Methodol. 2020;20:201.
Carter B, Law J, Hewitt J, Parmar KL, Boyle JM, Casey P, Maitra I, Pearce L, Moug SJ; ELF Study Group. Association between preadmission frailty and care level at discharge in older adults undergoing emergency laparotomy. Br J Surg. 2020;107:218-226.
CRC COVID Research Collaborative. The impact of the COVID-19 pandemic on colorectal cancer service provision. Br J Surg. 2020; 107:e521–e522.
McSorley ST, Anderson JH, Whittle T, Roxburgh CS, Horgan PG, McMillan DC, Steele CW. The impact of preoperative systemic inflammation on the efficacy of intravenous iron infusion to correct anaemia prior to surgery for colorectal cancer. Perioperative Med 2020;9:17
McSorley ST, Tham A, Dolan RD, Steele CW, Ramsingh J, Roxburgh C, Horgan PG, McMillan DC. Perioperative Blood Transfusion is Associated with Postoperative Systemic Inflammatory Response and Poorer Outcomes Following Surgery for Colorectal Cancer. Ann Surg Oncol. 2020 Mar;27(3):833-843
Steele CW, Whittle T, Smith JJ. Review: KRAS mutations are influential in driving hepatic metastases and predicting outcome in colorectal cancer. Chin Clin Oncol. 2019 Oct;8(5):53.
2019
Golder AM, Steele CW, Conn D, MacKay GJ, McMillan DC, Horgan PG, Roxburgh CS, McSorley ST. Effect of preoperative oral antibiotics in combination with mechanical bowel preparation on inflammatory response and short-term outcomes following left-sided colonic and rectal resections. BJS Open. 2019;3:830-839.
Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell. 2019;36:319-336.e7.
McSorley S, Johnstone M, Steele CW, Roxburgh CSD, McMillan D, Horgan P, Mansouri D. Normocytic anaemia is associated with systemic inflammation and poorer survival in patients with colorectal cancer treated with curative intent. International Journal of Colorectal Disease 2019;34:401-408.
McSorley S, Tham A, Steele CW, Dolan R, Horgan P, McMillan D. Quantitative data on red cell measures of iron status and their relation to the magnitude of the systemic inflammatory response and survival in patients with colorectal cancer. EJSO 2019 Feb 27. pii: S0748-7983(19)30300-2.
Parmar KL, Law J, Carter B, Hewitt J, Boyle JM, Casey P, Maitra I, Farrell IS, Pearce L, Moug SJ; ELF Study Group. Frailty in Older Patients Undergoing Emergency Laparotomy: Results From the UK Observational Emergency Laparotomy and Frailty (ELF) Study. Ann Surg. 2019; 273: 709-718
Reader CS, Vallath S, Steele CW, Haider S, Brentnall A, Desai A, Moore KM, Jamieson NB, Chang D, Bailey P, Scarpa A, Lawlor R, Chelala C, Keyse SM, Biankin A, Morton JP, Evans TRJ, Barry ST, Sansom OJ, Kocher HM, Marshall JF. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J Pathol. 2019;249:332-342.
2018
McSorley S, Steele CW, McMahon A. Meta-analysis of oral antibiotics in combination with mechanical bowel preparation the day before surgery to reduce surgical site infections in elective colorectal surgery. BJS (Open) 2018; 2:185-194.
Senior Clinical Lecturer in Pancreatic Cancer
Introduction
Pancreatic cancer continues to be almost universally lethal and is predicted to soon become the second highest cause of cancer death. To date, there has been little improvement in overall outcomes, with very few effective therapies available. We do, however, see exceptional tumour responses occasionally, where patients derive significant benefits and have better outcomes. Thus, there is an urgent need to personalise our patient care and better identify the right treatment for each patient.
Most of the observations in pancreatic cancer biology can be explained through basic evolutionary principles: it is a complex cancer that is adaptive, highly capable to thrive in a resource constrained environment and uniquely able to evade anti-cancer therapy. But how do cancer cells optimise their fitness, at the expense of the host, to progress into this deadly cancer? And, what can we learn from studying the alterations in the tumour and its microenvironment in the context of its host system? These are central questions driving my research, using well-annotated patient samples in conjunction with patient-derived preclinical model systems to identify novel therapeutic approaches and candidate biomarkers that can be tested in clinical trials.
Clinically, I am an Honorary Consultant Medical Oncologist at the Beatson West of Scotland Cancer Centre treating patients with pancreatic cancer. The overall goal is to develop personalised therapeutic strategies that emanate from discoveries in both basic science and reverse translation from clinical observation.
Biography
Education and qualifications
2020 ECFMG Certification, United States Medical Licensing Examination
2017 Postgraduate Diploma in Oncology, Institute of Cancer Research, London, UK
2017 Certificate of Completion of Training in Medical Oncology- General Medical Council, UK
2012 MRCP(UK) Royal College of Physicians UK
2011 PhD Barts Cancer Institute, Queen Mary University of London, UK
2006 M.D. Faculty of Medicine, University of Utrecht, The Netherlands
Appointments
2020-present: Clinical Senior Lecturer in Pancreatic Cancer, CRUK Scotland Institute and School of Cancer Sciences, University of Glasgow, UK
Oncology Lead, Glasgow Precision Oncology Laboratory (GPOL),Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK
Honorary Consultant Medical Oncologist, Beatson West of Scotland Cancer Centre, NHS Greater Glasgow and Clyde, Glasgow, UK
2020–2020 Consultant Medical Oncologist, Edinburgh Cancer Centre, Edinburgh, UK
2017–2020 Donaldson Translational Research Fellow, Cold Spring Harbor Laboratory, NY, USA
2017–2020 Instructor in Medical Oncology, Northwell Health, NY, USA
2019–2020 Clinical Observer Fellowship, Memorial Sloan-Kettering Cancer Center, NY, USA
2017–2020 Honorary Clinical Senior Lecturer, Imperial College London, UK
2013–2017 NIHR Academic Clinical Lecturer, Imperial College London, UK
2013–2013 Specialist Registrar Medical Oncology, Royal Marsden NHS Foundation Trust, London, UK
2011–2013 Core Medical Training, Ipswich Hospital NHS Trust, Ipswich, UK
2009–2010 Honorary Clinical Fellow Acute Medicine, Barts and The London NHS Trust, London, UK
2007–2011 Clinical Research Fellow, Centre for Tumour Biology, Barts Cancer Institute, London, UK
Current committee membership
Member of the Independent Data Monitoring Committee for STARPAC2 (PRIMUS-005); UK
Member of the Global Alliance for Genomics and Health (GA4GH) Equity, Diversity, and Inclusion (EDI) Advisory Group; International
Member of Lustgarten Foundation Translational Advisory Group; USA
Co-chair of Trial Management Group for PRIMUS-004; UK
Member of Trial Management Group for PASS-01; USA and Canada
Co-chair of Polyethnic-1000 Steering Committee; USA
Affiliate member of New York Genome Center Cancer Group; USA
Member of ICGC – ARGO Tissue and Clinical Annotation Working Group; International
Recent Publications
2023
Bergamini A, Ramaswami R, Froeling F, Papanastasopoulos P, Short D, Aguiar X, Savage PM, Sarwar N, Kaur B, Saso S, Fotopoulou C, Sharma A, Rustin GJS, Seckl M. Fertility outcomes following surgery and multiagent chemotherapy in malignant ovarian germ cell tumor survivors: a survey study. Int J Gynecol Cancer. 2023;33(11):1750-1756.
Chung T, Garcia L, Swamynathan MM, Froeling FEM, Trotman LC, Tuveson DA, Lyons SK.Internally Controlled and Dynamic Optical Measures of Functional Tumor Biology. Anal Chem. 2023; 95: 5661–5670
2022
Bryce AS, Dreyer SB, Froeling FEM, Chang DK. Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer. Cancers (Basel). 2022;14:5302
2021
Casolino R, Paiella S, Azzolina D, Beer PA, Corbo V, Lorenzoni G, Gregori D, Golan T, Braconi C, Froeling FEM, Milella M, Scarpa A, Pea A, Malleo G, Salvia R, Bassi C, Chang DK, Biankin AV. Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis. J Clin Oncol. 2021;39: 2617-2631
Dreyer SB, Upstill-Goddard R, Paulus-Hock V, Paris C, Lampraki EM, Dray E, Serrels B, Caligiuri G, Rebus S, Plenker D, Galluzzo Z, Brunton H, Cunningham R, Tesson M, Nourse C, Bailey UM, Jones M, Moran-Jones K, Wright DW, Duthie F, Oien K, Evers L, McKay CJ, McGregor GA, Gulati A, Brough R, Bajrami I, Pettitt S, Dziubinski ML, Candido J, Balkwill F, Barry ST, Grützmann R, Rahib L; Glasgow Precision Oncology Laboratory,; Australian Pancreatic Cancer Genome Initiative, Johns A, Pajic M, Froeling FEM, Beer P, Musgrove EA, Petersen GM, Ashworth A, Frame MC, Crawford HC, Simeone DM, Lord C, Mukhopadhyay D, Pilarsky C, Tuveson DA, Cooke SL, Jamieson NB, Morton JP, Sansom OJ, Bailey PJ, Biankin AV, Chang DK. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer. Gastroenterology. 2021;160(1):362-377.
Casolino R, Braconi C, Malleo G, Paiella S, Bassi C, Milella M, DreyerSB, Froeling FEM, Chang DK, Biankin AV, Golan T. Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine. Annals of Oncology. 2021;32:183-196.
Froeling FEM, Casolino R, Pea A, Biankin AV, Chang DK. Molecular Subtyping and Precision Medicine for Pancreatic Cancer. J Clin Med. 2021;10: 149
2020
Brunton H, Caligiuri G, Cunningham R, Upstill-Goddard R, Bailey UM, Garner IM, Nourse C, Dreyer SB, Jones M, Moran-Jones K, Wright DW, Paulus-Hock V, Nixon C, Thomson G, Jamieson NB, McGregor GA, Evers L, McKay CJ, Gulati A, Brough R, Bajrami I, Pettit S, Dziubinski ML, Barry ST, Grützmann R, Brown R, Curry E, Glasgow Precision Oncology Laboratory, Australian Pancreatic Cancer Genome Initiative, Pajic M, Musgrove EA, Petersen G, Shanks E, Ashworth A, Crawford HC, Simeone DM, Froeling FEM, Lord CJ, Mukhopadhyay D, Pilarsky C, Grimmond SE, Morton JP, Sansom OJ, Chang DK, Bailey P, Biankin AV. HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Reports. 2020;31(6):107625.
Chan-Seng-Yue M, Kim JC, Wilson GW, Ng K, Flores Figueroa F, O’Kane GM, Connor AA, Denroche RE, Grant RC, McLeod J, Wilson JM, Ho Jang G, Zhang A, Liang SB, Borgida A, Chadwick D, Kalimuthu S, Lungu I, Bartlett JMS, Krzyzanowski PM, Sandhu V, Tiriac H, Froeling FEM, Karasinska JM, Topham JT, Renouf DJ, Schaeffer DF, Jones SJM, Marra MA, Laskin J, Chetty R, Stein LD, Zogopoulos G, Haibe-Kains B, Campbell PJ, Tuveson DA, Knox JJ, Fischer SE, Gallinger S, Notta F. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumour evolution. Nat Genet. 2020;52(2):231-240.
Kocher HM, Basu B, Froeling FEM, Sarker D, Slater S, Carlin D, deSouza NM, De Paepe KN, Goulart MR, Hughes C, Imrali A, Roberts R, Pawula M, Houghton R, Lawrence C, Yogeswaran Y, Mousa K, Coetzee C, Sasieni P, Prendergast A, Propper DJ. Phase I clinical trial repurposing all-trans retinoic acid (ATRA) as a stromal targeting 1 agent for pancreatic cancer (STARPAC). Nat Commun. 2020;11(1):4841.
2019
Froeling FEM, Swamynathan MM, Deschênes A, Chio IIC, Brosnan E, Yao MA, Alagesan P, Lucito M, Li J, Chang AY, Trotman LC, Belleau P, Park Y, Rogoff HA, Watson JD, Tuveson DA. Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death. Clin Cancer Res. 2019;25(23):7162-7174.
Froeling FEM, Ramaswami R, Papanastasopoulos P, Kaur B, Sebire NJ, Short D, Fisher RA, Sarwar N, Wells M, Singh K, Ellis L, Horsman JM, Winter MC, Tidy J, Hancock BW, Seckl MJ. Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours. Br J Cancer. 2019;120(6):587-594.
2018
Tiriac H, Belleau P, Engle DD, Plenker D, Deschênes A, Somerville TDD, Froeling FEM, Burkhart RA, Denroche RE, Jang GH, Miyabayashi K, Young CM, Patel H, Ma M, LaComb JF, Palmaira RLD, Javed AA, Huynh JC, Johnson M, Arora K, Robine N, Shah M, Sanghvi R, Goetz AB, Lowder CY, Martello L, Driehuis E, LeComte N, Askan G, Iacobuzio-Donahue CA, Clevers H, Wood LD, Hruban RH, Thompson E, Aguirre AJ, Wolpin BM, Sasson A, Kim J, Wu M, Bucobo JC, Allen P, Sejpal DV, Nealon W, Sullivan JD, Winter JM, Gimotty PA, Grem JL, DiMaio DJ, Buscaglia JM, Grandgenett PM, Brody JR, Hollingsworth MA, O'Kane GM, Notta F, Kim E, Crawford JM, Devoe C, Ocean A, Wolfgang CL, Yu KH, Li E, Vakoc CR, Hubert B, Fischer SE, Wilson JM, Moffitt R, Knox J, Krasnitz A, Gallinger S, Tuveson DA. Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov. 2018;8(9):1112-1129.
Ul-Haq I, Dalla Pria A, Suardi E, Pinato DJ, Froeling FEM, Forni J, Randell P, Bower M. Blood Epstein-Barr virus DNA does not predict outcome in advanced HIV-associated Hodgkin lymphoma. Med Oncol. 2018;35(4):53.
Froeling FEM, Tuveson DA. Pancreatic cancer foiled by a switch of tumour subtype. Nature. 2018;557(7706):500-501.
Introduction
The Cagan laboratory uses Drosophila to explore the biology of therapeutics. Data from several laboratories including our own have highlighted the role of genomic complexity in cancer drug resistance. To explore this, we have developed genomically complex fly models of cancer (colorectal, thyroid, breast, lung) and rare genetic diseases (primarily RASopathies). These act as a starting point for our work in mammalian models, both directly and with our collaborators.
Each personalised fly 'avatar' line models a different patient, each with typically 5-15 altered genes. While targeted therapies are effective in '2-hit' models, 12-hit models—even with many of the same cancer drivers—are often resistant to these same therapies.
We are leveraging our fly platform containing dozens of avatar lines to explore changes in transformation that come with genomic complexity. This has led to an ongoing 'fly-to-bedside' clinical trial in which 'personalised fly avatars' are used to identify therapeutic cocktails unique to each patient.
Further, we are working with chemists to address disease complexity through drug cocktails and through building a new generation of 'network-based' novel lead compounds that address tumour and rare disease complexity through multi-targeted 'polypharmacology'.
Other funding:
Lab Report
Key Publications
Das TK, Gatto J, Mirmira R, Hourizadeh E, Kaufman D, Gelb BD, Cagan R. Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy. iScience. 2021;24(4):102306.
Bangi E, Smibert P, Uzilov AV, Teague AG, Gopinath S, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon WJ, Malyshev D, Laspina D, Selkridge I, Wang H, Gomez J, Mascarenhas J, Moe AS, Lau CY, Taik P, Pandya C, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Ang C, Schadt EE, Posner MR, Cagan RL. A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma. iScience. 2021;24(3):102212.
Bangi E, Ang C, Smibert P, Uzilov A, Teague A, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon W, Malyshev D, Laspina D, Selkridge I, Rainey H, Moe A, Lau CY, Taik P, Wilck E, Bhardwaj A, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Schadt E, Posner M, and Cagan R. A Personalized Platform Identifies Trametinib Plus Zoledronate For A Patient With KRAS-Mutant Metastatic Colorectal Cancer Science Advances 2019;5(5):eaav6528.
Ung P, Sonoshita M, Scopton A, Dar A, Cagan R, Schlessinger A. Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network. PLoS Comput Biol. 2019; 15:e1006878.
Das TK, Esernio J, Cagan R. Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance. Cancer Research 2018;78:4344-59.
*Sonoshita, M., *Scopton, A., Ung, P., Murray, M., Silber, L., Maldonado, A., Real, A., Schlessinger, A., **Cagan, R., **Dar, A. A Whole Animal Platform to Advance A Clinical Kinase Inhibitor Into New Disease Space. Nature Chemical Biology 2018;14:291-98. *Co-first authors; **co-corresponding authors.
Hirabayashi S, Baranski T, and. Cagan R. Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance Through Wingless Signaling. Cell 2013;154:664-75.
*Dar AC, *Das T, Shokat KM, and Cagan R. Chemical Genetic Discovery of Targets and Anti-targets for Polypharmacological Treatment of Cancer. Nature 2012;486:80-4. *Co-first authors.
Biography
Education and qualifications
1989-2003: Postdoctoral Fellow, Dr S. Lawrence Zipurski, UCLA, USA
1989: PhD, Developmental Neurobiology, Dr Donald Ready, Princeton University, USA
1982: B.A., Biology, University of Chicago, USA
Appointments
2020-present: Scientific Director, Wolfson Wohl Cancer Research
2020-present: Regius Professor of Precision Medicine, University of Glasgow
2013-2020: Founder and Director, Center for Personalized Cancer Therapeutics, Icahn School of Medicine at Mount Sinai, USA
2007-2020: Professor, Dept. of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, USA
2005-2015: Co-founder, Board of Directors of Medros Inc., USA
1993-2007: Advanced from Assistant Professor to Full Professor, Washington University School of Medicine, USA
Current committee membership
Board member, Athena Swan/VOICE Diversity Committee
Member, School of Cancer Sciences: Fellowship & Career Development Committee
Member, Beatson Senior Management Team
External Advisory Board, University of Miami Sylvester Cancer Center
Scientific Advisory Board, Pershing Square Prize
International Thyroid Oncology Group
Editorial Board, Disease Models and Mechanisms
Honours and awards
Regius Professorship of Precision Medicine
Fellow of the Royal Society
Dean’s Healthcare System Team Science Award 2017, Icahn School of Medicine at Mount Sinai, USA
Salk Outstanding Postdoctoral Fellow 1992
American Cancer Society Senior Postdoctoral Fellowship 1992
National Institute of General Medical Sciences/National Institutes of Health postdoctoral grant 1989
Recent Publications
2024
Cong B, Cagan RL. Cell competition and cancer from Drosophila to mammals. Oncogenesis. 2024(1):1.
2023
Cong B, Thakur T, Uribe AH, Stamou E, Gopinath S, Maddocks O, Cagan R. Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism. bioRxiv. 2023:2023.2012.2021.572817.
Rhodes SD, McCormick F, Cagan RL, Bakker A, Staedtke V, Ly I, Steensma MR, Lee SY, Romo CG, Blakeley JO, Sarin KY. RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights. J Invest Dermatol. 2023;143: 1358-1368
Staedtke V, Topilko P, Le LQ, Grimes K, Largaespada DA, Cagan RL, Steensma MR, Stemmer-Rachamimov A, Blakeley JO, Rhodes SD, Ly I, Romo CG, Lee SY, Serra E. Existing and Developing Preclinical Models for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas. J Invest Dermatol. 2023;143: 1378-1387
2022
Cagan R, Shokat K. Drugging the undruggable: Ross Cagan interviews Kevan Shokat. Dis Model Mech. 2022;15: dmm049468
2021
Bangi E, Smibert P, Uzilov AV, Teague AG, Gopinath S, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon WJ, Malyshev D, Laspina D, Selkridge I, Wang H, Gomez J, Mascarenhas J, Moe AS, Lau CY, Taik P, Pandya C, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Ang C, Schadt EE, Posner MR, Cagan RL. A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma. iScience. 2021;24(3):102212.
Das TK, Gatto J, Mirmira R, Hourizadeh E, Kaufman D, Gelb BD, Cagan R. Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy. iScience. 2021;24(4):102306.
Padash Barmchi M, Thomas M, Thatte JV, Vats A, Zhang B, Cagan RL, Banks L. Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6. Sci Rep. 2021;11:1111.
Xiong Z, Jeon M, Allaway RJ, Kang J, Park D, Lee J, Jeon H, Ko M, Jiang H, Zheng M, Tan AC, Guo X, Dang KK, Tropsha A, Hecht C, Das TK, Carlson HA, Abagyan R, Guinney J, Schlessinger A, Cagan R. Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge. PLoS Comput Biol. 2021;17:e1009302.
Posner M, Cagan R. Interdisciplinary case study: from fly-to-bedside, translating basic research to the clinic. iScience. 24:102279.
2020
Hirabayashi S, Cagan R. Systemic Regulation of Local Cell Competition. Dev Cell. 2020;53:371-372.
2019
Bangi E, Ang C, Smibert P, Uzilov A, Teague A, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon W, Malyshev D, Laspina D, Selkridge I, Rainey H, Moe A, Lau CY, Taik P, Wilck E, Bhardwaj A, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Schadt E, Posner M, and Cagan R. A Personalized Platform Identifies Trametinib Plus Zoledronate For A Patient With KRAS-Mutant Metastatic Colorectal Cancer Science Advances 2019;5(5):eaav6528.
Kuleshov MV, Diaz JEL, Flamholz ZN, Keenan AB, Lachmann A, Wojciechowicz ML, Cagan RL, Ma'ayan A. modEnrichr: a suite of gene set enrichment analysis tools for model organisms. Nucleic Acids Res. 2019 May 9. pii: gkz347.
Ung P, Sonoshita M, Scopton A, Dar A, Cagan R, Schlessinger A. Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network. PLoS Comput Biol. 2019; 15:e1006878.
Cagan RL, Zon LI, White RM. Modeling Cancer with Flies and Fish. Developmental Cell 2019;49(3):317-24
2018
Das TK, Cagan RL. Non-mammalian models of multiple endocrine neoplasia type 2. Endocr Relat Cancer. 2018;25:T91-T104
Das TK, Esernio J, Cagan R. Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance. Cancer Research 2018;78:4344-59.
*Sonoshita, M., *Scopton, A., Ung, P., Murray, M., Silber, L., Maldonado, A., Real, A., Schlessinger, A., **Cagan, R., **Dar, A. A Whole Animal Platform to Advance A Clinical Kinase Inhibitor Into New Disease Space. Nature Chemical Biology 2018;14:291-98. *Co-first authors; **co-corresponding authors.
2017
Cagan R, Meyer P. Rethinking cancer: current challenges and opportunities in cancer KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub.Dis Model Mech. 2017;10:349-52.
Das T, Cagan R. KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub. Cell Reports 2017 Sep 5;20:2368-2383.
Schlessinger A, Abagyan R, Carlson HA, Dang KK, Guinney J, Cagan RL. Modeling Human Cancers in Drosophila Drug Community Challenge. Cell Chem Biol. 2017 Dec 21;24:1434-5
Sonoshita M and Cagan R. Modeling Human Cancers in Drosophila. Curr Top Dev Biol. 2017;121:287-309.
2016
Bangi E, Murgia C, Teague A, Sansom O., and Cagan R. Functional exploration of colorectal cancer genomes using Drosophila. Nature Communications 2016;7:13615.
Levine B and Cagan R. Drosophila Lung Cancer Models Identify Trametinib Plus Statin as a Candidate Therapeutic. Cell Reports 2016;14:1477-87.
Levinson S and Cagan R. Drosophila Cancer Models Identify Functional Differences between Ret Fusions.Cell Rep. 2016;16:3052-61.
Introduction
Remarkable cancer cell metabolic flexibility and plasticity enable tumours to grow and combat chemotherapy. Mitochondria are essential organelles that support tumour adaptation to altered metabolic demands and environmental challenges. Accordingly, mitochondrial form and function are dynamically reprogrammed during tumorigenesis. For instance, the levels of key mitochondrial inner membrane proteins, including metabolite transporters, are fine tuned in response to nutrient and oxygen availability to support cancer cell proliferation and survival.
Metabolite transporter proteins are required to exchange small molecules including amino acids and nucleotides between the mitochondria and the rest of the cell. The tightly regulated coupling of cytosolic and mitochondrial metabolic reactions across the inner mitochondrial membrane represents an essential but poorly understood facet of tumour metabolism. Our goal is to identify mitochondrial metabolite transporters that control cancer progression using genetic screening approaches in 3D tumour models combined with genetically engineered mouse models. We will also investigate how regulated mitochondrial nucleotide transport and metabolism contribute to tumorigenesis and cancer cell responses to nucleotide-analogue chemotherapy. These studies will improve our basic understanding of mitochondrial reprogramming in tumours and may identify novel therapeutic targets for cancers that depend on metabolic flexibility and plasticity, including pancreatic cancer.
Biography
Education and qualifications
2013: PhD, School of Biochemistry, University of Bristol
2009: BSc, Biochemistry, University of Bristol
Appointments
2021-present: CRUK Career Development Fellow, Cancer Research UK Scotland Institute
2018-2021: Postdoctoral Researcher, Max Planck Institute for Biology of Ageing, Cologne, Germany
2014-2018: Postdoctoral Researcher, CECAD, Cologne, Germany
2013-2014: Postdoctoral Researcher, Department of Biochemistry, University of Bristol, UK
Honours and Awards
2016 Humboldt Research Fellowship for Postdoctoral Researchers
2015 EMBO Long-Term Postdoctoral Fellowship
Recent Publications
2023
Grotehans N, McGarry L, Nolte H, Xavier V, Kroker M, Narbona-Pérez Á J, Deshwal S, Giavalisco P, Langer T, MacVicar T. Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression. Embo j. 2023;10.15252/embj.2022113256:e113256.
2021
Murschall LM, Peker E, MacVicar T, Langer T, Riemer J. Protein Import Assay into Mitochondria Isolated from Human Cells. Bio Protoc. 2021;11(12):e4057.
Sprenger HG*, MacVicar T*, Bahat A, Fiedler KU, Hermans S, Ehrentraut D, Ried K, Milenkovic D, Bonekamp N, Larsson NG, Nolte H, Giavalisco P, Langer T. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity. Nat Metab. 2021;3(5):636-650.*equal contribution
Willenborg S, Sanin DE, Jais A, Ding X, Ulas T, Nuchel J, Popovic M, MacVicar T, Langer T, Schultze JL, et al. (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab 33, 2398-2414 e2399. 1
Bahat A*, MacVicar T*, Langer T. Metabolism and Innate Immunity Meet at the Mitochondria. Front Cell Dev Biol. 2021;9:720490.*equal contribution
MacVicar T, Langer T. Mechanometabolism: Mitochondria promote resilience under pressure. Curr Biol. 2021;31(13):R859-r861.
2020
Murschall LM, Gerhards A, MacVicar T, Peker E, Hasberg L, Wawra S, Langer T, Riemer J. The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import. BMC Biol. 2020;18(1):96.
Ohba Y, MacVicar T, Langer T. Regulation of mitochondrial plasticity by the i-AAA protease YME1L. Biol Chem. 2020;401(6-7):877-890.
Wang Z, Liu F, Fan N, Zhou C, Li D, Macvicar T, Dong Q, Bruns CJ, Zhao Y. Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies. Front Oncol. 2020;10:589508.
2019
MacVicar T*, Ohba Y*, Nolte H, Mayer FC, Tatsuta T, Sprenger HG, Lindner B, Zhao Y, Li J, Bruns C, Krüger M, Habich M, Riemer J, Schwarzer R, Pasparakis M, Henschke S, Brüning JC, Zamboni N, Langer T. Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature. 2019;575(7782):361-365. *equal contribution
Richter F, Dennerlein S, Nikolov M, Jans DC, Naumenko N, Aich A, MacVicar T, Linden A, Jakobs S, Urlaub H, Langer T, Rehling P. ROMO1 is a constituent of the human presequence translocase required for YME1L protease import. J Cell Biol. 2019;218(2):598-614.
Sprenger HG, Wani G, Hesseling A, König T, Patron M, MacVicar T, Ahola S, Wai T, Barth E, Rugarli EI, Bergami M, Langer T. Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol Med. 2019;11(1).
Ahola S, Langer T, MacVicar T. Mitochondrial Proteolysis and Metabolic Control. Cold Spring Harb Perspect Biol. 2019;11(7).
2018
Nolte H, MacVicar TD, Tellkamp F, Krüger M. Instant Clue: A Software Suite for Interactive Data Visualization and Analysis. Sci Rep. 2018;8(1):12648.
2016
Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, Stenzel W, Gräf R, van den Heuvel L, Ropers HH, Wienker TF, Hübner C, Langer T, Kaindl AM. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. 2016;5.
MacVicar T, Langer T. OPA1 processing in cell death and disease - the long and short of it. J Cell Sci. 2016;129(12):2297-2306.
2015
MacVicar TD*, Mannack LV*, Lees RM, Lane JD. Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells. Int J Mol Sci. 2015;16(6):13356-13380. *equal contribution
2014
MacVicar TD, Lane JD. Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation. J Cell Sci. 2014;127(Pt 10):2313-2325.
2013
MacVicar T. Mitophagy. Essays Biochem. 2013;55:93-104.
2012
Betin VM, MacVicar TD, Parsons SF, Anstee DJ, Lane JD. A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress. Autophagy. 2012;8(4):664-676.
Introduction
In every human cell, the expression of 25,000 genes is precisely regulated to generate the spectrum of cell types required through development and into the adult. We are interested in the signalling pathways that coordinate and regulate gene expression, and how dysregulation of these pathways is a cause or consequence of disease. Our aim is to understand how gene expression is regulated in health and disease, and to use this knowledge to develop and refine therapeutic approaches.
Our focus is on the RNA cap, a structure found on pre-mRNA and non-coding RNA that protects RNA and recruits factors involved in processing and translation. A series of RNA capping enzymes catalyses cap formation, predominantly as the transcript is being synthesised. We are interested in how these RNA capping enzymes are regulated during development and in the adult, and the impact that this has on gene expression. Currently, we are investigating RNA cap regulation in embryonic stem cell differentiation, during T cell activation and following oncogene dysregulation in cancer models.
Regulation of the RNA cap can have potent effects on cell function and fate decisions via the regulation of specific gene families. We characterise the biochemical configuration of capping enzyme complexes in different cell types or disease states, follow how these configurations change during differentiation and disease, and determine the impact on gene expression and cell function and fate decisions.
Email
Lab Report
pdf Cowling Lab Report (231 KB)
Key Publications
Galloway A, Kaskar A, Ditsova D, Atrih A, Yoshikawa H, Gomez-Moreira C, Suska O, Warminski M, Grzela R, Lamond AI, Darzynkiewicz E, Jemielity J, Cowling VH. Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation. Nucleic Acids Res. 2021;49(12):6722-6738.
Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O, Cowling VH. mRNA Cap Methyltransferase, RNMT-RAM, Promotes RNA Pol II-Dependent Transcription. Cell Rep. 2018;23(5):1530-1542.
Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016;44(21):10423-10436.
Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. mRNA Cap Methylation in Pluripotency and Differentiation. Cell Rep. 2016;16(5):1352-1365.
Aregger M, Kaskar A, Varshney D, Fernandez-Sanchez ME, Inesta-Vaquera FA, Weidlich S, Cowling VH. CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription. Mol Cell. 2016;61(5):734-746.
Biography
Education and qualifications
2002: PhD, Cancer Research UK London Research Institute/UCL - Caspase activation during programmed cell death
1997: BA Natural Sciences, Cambridge University
Appointments
2022-present: Senior Group Leader, CRUK Scotland Institute, Glasgow, UK and Chair of Biology (Full Professor), University of Glasgow, UK
2017-2022: Deputy Head of Centre for Gene Regulation and Expression, University of Dundee, UK
2016: Chair of Biology (Full Professor), University of Dundee, UK
2007-2022: Group Leader, School of Life Sciences, University of Dundee, UK - Regulation of RNA cap in health and disease
2003-2007: Postdoctoral research at Princeton University and Darmouth College, USA - Myc oncogenes: mechanisms and function in breast cancers
Awards and fellowships
Wellcome Trust Investigator Award, 2020
Fellow of the Royal Society of Edinburgh, 2019
Wolfson Royal Society Research Merit Award, 2018
European Research Council (ERC) Consolidator Award, 2017
Fellow of the Royal Society of Biology (UK), 2016
British Society of Cell Biology Women in Cell Biology Award, 2015
European Molecular Biology Organisation (EMBO) Young Investigator, 2014
Medical Research Council UK (MRC) Senior Fellowship, 2013
Lister Institute Prize Fellowship, 2011
Medical Research Council UK (MRC) Career Development Award, 2007
Current committee membership
British Society of Cell Biology Committee
Wellcome Trust Expert Review Group
Volkswagen Foundation Momentum Panel
Royal Society of Edinburgh Fellow Selection Panel
Recent Publications
2023
Liang S, Almohammed R, Cowling VH. The RNA cap methyltransferases RNMT and CMTR1 co-ordinate gene expression during neural differentiation. Biochem Soc Trans. 2023;10.1042/bst20221154.
2022
Liang S, Silva JC, Suska O, Lukoszek R, Almohammed R, Cowling VH. CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells. Nucleic Acids Res. 2022;50:2905-2922.
Osborne MJ, Volpon L, Memarpoor-Yazdi M, Pillay S, Thambipillai A, Czarnota S, Culjkovic-Kraljacic B, Trahan C, Oeffinger M, Cowling VH, Borden KLB. Identification and Characterization of the Interaction Between the Methyl-7-Guanosine Cap Maturation Enzyme RNMT and the Cap-Binding Protein eIF4E. J Mol Biol. 2022;434:167451.
2021
Bage MG, Almohammed R, Cowling VH, Pisliakov AV. A novel RNA pol II CTD interaction site on the mRNA capping enzyme is essential for its allosteric activation. Nucleic Acids Res. 2021;49(6):3109-3126.
Basu S, Mak T, Ulferts R, Wu M, Deegan T, Fujisawa R, Tan KW, Lim CT, Basier C, Canal B, Curran JF, Drury LS, McClure AW, Roberts EL, Weissmann F, Zeisner TU, Beale R, Cowling VH, Howell M, Labib K, Diffley JFX. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase. Biochem J. 2021;478(13):2481-2497.
Galloway A, Kaskar A, Ditsova D, Atrih A, Yoshikawa H, Gomez-Moreira C, Suska O, Warminski M, Grzela R, Lamond AI, Darzynkiewicz E, Jemielity J, Cowling VH. Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation. Nucleic Acids Res. 2021;49(12):6722-6738.
Pearson L-A, Green CJ, Lin D, Petit A-P, Gray DW, Cowling VH, Fordyce EAF. Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry. SLAS DISCOVERY: Advancing the Science of Drug Discovery. 2021;26(6):749-756.
Borden KLB, Culjkovic-Kraljacic B, Cowling VH. To Cap it all Off, Again: Dynamic Capping and Recapping of Coding and Non-coding RNAs to Control Transcript Fate and Biological Activity Cell Cycle. 2021; 20(14):1347-1360.
2020
Culjkovic-Kraljacic B, Skrabanek L, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L, Borden KLB. The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts. Proceedings of the National Academy of Sciences. 2020;117(43):26773-26783.
Galloway A, Atrih A, Grzela R, Darzynkiewicz E, Ferguson MAJ, Cowling VH. CAP-MAP: cap analysis protocol with minimal analyte processing, a rapid and sensitive approach to analysing mRNA cap structures. Open Biol. 2020;10(2):190306.
Kasprzyk R, Fido M, Mamot A, Wanat P, Smietanski M, Kopcial M, Cowling VH, Kowalska J, Jemielity J. Direct High-Throughput Screening Assay for mRNA Cap Guanine-N7 Methyltransferase Activity. Chemistry. 2020;26(49):11266-11275.
2019
Bueren-Calabuig JA, M GB, Cowling VH, Pisliakov AV. Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations. Nucleic Acids Res. 2019;47(16):8675-8692.
Dunn S, Lombardi O, Lukoszek R, Cowling VH. Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells. Open Biol. 2019;9(4):190052.
Cowling VH. CAPAM: The mRNA Cap Adenosine N6-Methyltransferase. Trends in Biochemical Sciences. 2019;44:183-185.
Galloway A, Cowling VH. mRNA cap regulation in mammalian cell function and fate. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 2019;1862:270-279.
2018
Inesta-Vaquera F, Chaugule VK, Galloway A, Chandler L, Rojas-Fernandez A, Weidlich S, Peggie M, Cowling VH. DHX15 regulates CMTR1-dependent gene expression and cell proliferation. Life Sci Alliance. 2018;1(3):e201800092.
Kelner A, Tinti M, Guther MLS, Foth BJ, Chappell L, Berriman M, Cowling VH, Ferguson MAJ. The mRNA cap methyltransferase gene TbCMT1 is not essential in vitro but is a virulence factor in vivo for bloodstream form Trypanosoma brucei. PLoS One. 2018;13(7):e0201263.
Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O, Cowling VH. mRNA Cap Methyltransferase, RNMT-RAM, Promotes RNA Pol II-Dependent Transcription. Cell Rep. 2018;23(5):1530-1542.
Jantsch MF, Quattrone A, O'Connell M, Helm M, Frye M, Macias-Gonzales M, Ohman M, Ameres S, Willems L, Fuks F, Oulas A, Vanacova S, Nielsen H, Bousquet-Antonelli C, Motorin Y, Roignant JY, Balatsos N, Dinnyes A, Baranov P, Kelly V, Lamm A, Rechavi G, Pelizzola M, Liepins J, Holodnuka Kholodnyuk I, Zammit V, Ayers D, Drablos F, Dahl JA, Bujnicki J, Jeronimo C, Almeida R, Neagu M, Costache M, Bankovic J, Banovic B, Kyselovic J, Valor LM, Selbert S, Pir P, Demircan T, Cowling V, Schäfer M, Rossmanith W, Lafontaine D, David A, Carre C, Lyko F, Schaffrath R, Schwartz S, Verdel A, Klungland A, Purta E, Timotijevic G, Cardona F, Davalos A, Ballana E, D OC, Ule J, Fray R. Positioning Europe for the EPITRANSCRIPTOMICS challenge. RNA Biol.2018; 15:829-831.
2017
Dunn S, Lombardi O, Cowling VH. c-Myc co-ordinates mRNA cap methylation and ribosomal RNA production. Biochem J. 2017;474(3):377-384.
Aregger M, Cowling VH. Regulation of mRNA capping in the cell cycle. RNA biology. 2017:14:11-14.
Inesta-Vaquera F, Cowling VH. Regulation and function of CMTR1-dependent mRNA cap methylation. Wiley Interdiscip Rev RNA. 2017; 8:ed2017.
2016
Aregger M, Kaskar A, Varshney D, Fernandez-Sanchez ME, Inesta-Vaquera FA, Weidlich S, Cowling VH. CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription. Mol Cell. 2016;61(5):734-746.
Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. mRNA Cap Methylation in Pluripotency and Differentiation. Cell Rep. 2016;16(5):1352-1365.
Lombardi O, Varshney D, Phillips NM, Cowling VH. c-Myc deregulation induces mRNA capping enzyme dependency. Oncotarget. 2016;7(50):82273-82288.
Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016;44(21):10423-10436.
Young DF, Andrejeva J, Li X, Inesta-Vaquera F, Dong C, Cowling VH, Goodbourn S, Randall RE. Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family. J Virol. 2016;90(20):9446-9456.
Introduction
New therapies that target immune responses to kill tumours are an area of rapid growth and hope. While immune checkpoint blockade therapy has led to dramatic improvement for some patients, it still is not applicable for the majority of people affected by cancer. Challenges for immune therapies include poor immune infiltration of tumours, an inhibitory tumour microenvironment as well as immune-related toxicities.
The immune system protects us from infectious agents such as bacteria, viruses and fungi, as well as from malignant growth of our own tissues. Our lab is interested in the intersection between anti-bacterial and anti-tumour responses. Our bodies have both positive (commensals) and negative (pathogenic) interactions with bacteria. On the one hand, microbes that form our gut microbiota are important for instructing and regulating our immune system; While on the other, pathogenic or opportunistic microbes can deviate and manipulate our immune responses to aid their survival and spread, and even be involved in pro-tumourigenic processes.
The concept of bacterial cancer therapy dates to William Coley, who developed ‘Coley’s toxins’, a preparation of heat killed bacteria injected into tumours. Our work largely focuses on the use of live-attenuated Salmonella as a cancer therapy; we are dissecting the mechanisms by which attenuated Salmonella treatment leads to tumour regression, looking at the adaptation of the bacteria to the tumour environment, and the effects on cancer cells and on immune responses. With a detailed mechanistic understanding of bacterial therapy, we aim to achieve optimal engineering of Salmonella to advance towards clinical application.
Lab Report
Key Publications
Copland A, Mackie GM, Scarfe L, Lecky DAJ, Gudgeon N, McQuade R, Ono M, Barthel M, Hardt W-D, Ohno H, Dimeloe S, Bending D, Maslowski KM. Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. bioRxiv. 2023;10.1101/2023.01.12.523780:2023.2001.2012.523780.
Mackie GM, Copland A, Takahashi M, Nakanishi Y, Everard I, Kato T, Oda H, Kanaya T, Ohno H, Maslowski KM. Bacterial cancer therapy in autochthonous colorectal cancer affects tumor growth and metabolic landscape. JCI Insight. 2021;6.
Maslowski KM. Metabolism at the centre of the host-microbe relationship. Clin Exp Immunol. 2019;197:193-204.
Allam R, Maillard MH, Tardivel A, Chennupati V, Bega H, Yu CW, Velin D, Schneider P, Maslowski KM. Epithelial NAIPs protect against colonic tumorigenesis. J Exp Med. 2015;212:369-383
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282-1286.
Biography
Education and qualifications
2011: PhD, University of New South Wales, Sydney, Australia; Supervisor: Prof Charles Mackay, Project: The role of GPR43 in the immune system: a novel connection between diet, gut microbiota and immune function
2006: BSc with Honours, Molecular Biology, Murdoch University, Perth, Australia
2005: BSc, Molecular Biology, Murdoch University, Perth, Australia
Appointments
2023-present: Beatson Research Fellow, CRUK Career Development Fellow, CRUK Scotland Institute, Glasgow, UK
2022-2023: Associate Professor and CRUK Career Establishment Fellow, Institute of Immunology and Immunotherapy, University of Birmingham, UK
2017-2022: Birmingham Fellow and CRUK Career Establishment Fellow, Institute of Immunology and Immunotherapy, University of Birmingham, UK
2014-2017: Postdoctoral Researcher with Prof Hiroshi Ohno, RIKEN, Centre for Integrative Medical Sciences, Yokohama, Japan
2011-2014: Postdoctoral Researcher with Prof Jürg Tschopp, Department of Biochemistry, University of Lausanne, Switzerland
2007-2007: Research Assistant with Prof Charles Mackay, Garvan Institute of Medical Research, Sydney, Australia
Recent Publications
2023
Copland A, Mackie GM, Scarfe L, Lecky DAJ, Gudgeon N, McQuade R, Ono M, Barthel M, Hardt W-D, Ohno H, Dimeloe S, Bending D, Maslowski KM. Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. bioRxiv. 2023;10.1101/2023.01.12.523780:2023.2001.2012.523780.
Fisch D, Pfleiderer MM, Anastasakou E, Mackie GM, Wendt F, Liu X, Clough B, Lara-Reyna S, Encheva V, Snijders AP, Bando H, Yamamoto M, Beggs AD, Mercer J, Shenoy AR, Wollscheid B, Maslowski KM, Galej WP, Frickel EM. PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection. Science. 2023;382(6666):eadg2253.
2022
Bishop EL, Gudgeon NH, Mackie GM, Chauss D, Roberts J, Tennant DA, Maslowski KM, Afzali B, Hewison M, Dimeloe S. 1,25-Dihydroxyvitamin D3 suppresses CD4(+) T-cell effector functionality by inhibition of glycolysis. Immunology. 2022;166:299-309.
Bombaci G, Sarangdhar MA, Andina N, Tardivel A, Yu EC, Mackie GM, Pugh M, Ozan VB, Banz Y, Spinetti T, Hirzel C, Youd E, Schefold JC, Taylor G, Gazdhar A, Bonadies N, Angelillo-Scherrer A, Schneider P, Maslowski KM, Allam R. LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity. Life Sci Alliance. 2022;5.
Elliot TAE, Jennings EK, Lecky DAJ, Rouvray S, Mackie GM, Scarfe L, Sheriff L, Ono M, Maslowski KM, Bending D. Nur77-Tempo mice reveal T cell steady state antigen recognition. Discov Immunol. 2022;1:kyac009.
2021
Elliot TAE, Jennings EK, Lecky DAJ, Thawait N, Flores-Langarica A, Copland A, Maslowski KM, Wraith DC, Bending D. Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength. Immunity. 2021;54:2481-2496.e2486.
Mackie GM, Copland A, Takahashi M, Nakanishi Y, Everard I, Kato T, Oda H, Kanaya T, Ohno H, Maslowski KM. Bacterial cancer therapy in autochthonous colorectal cancer affects tumor growth and metabolic landscape. JCI Insight. 2021;6.
Scarfe L, Mackie GM, Maslowski KM. Inflammasome-independent functions of NAIPs and NLRs in the intestinal epithelium. Biochem Soc Trans. 2021;49:2601-2610.
2020
Sasaki N, Miyamoto K, Maslowski KM, Ohno H, Kanai T, Sato T. Development of a Scalable Coculture System for Gut Anaerobes and Human Colon Epithelium. Gastroenterology. 2020;159:388-390.e385.
2019
Maslowski KM. Metabolism at the centre of the host-microbe relationship. Clin Exp Immunol. 2019;197:193-204.
2018
Chennupati V, Veiga DF, Maslowski KM, Andina N, Tardivel A, Yu EC, Stilinovic M, Simillion C, Duchosal MA, Quadroni M, Roberts I, Sankaran VG, MacDonald HR, Fasel N, Angelillo-Scherrer A, Schneider P, Hoang T, Allam R. Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation. J Clin Invest. 2018;128:1597-1614.
2015
Allam R, Maillard MH, Tardivel A, Chennupati V, Bega H, Yu CW, Velin D, Schneider P, Maslowski KM. Epithelial NAIPs protect against colonic tumorigenesis. J Exp Med. 2015;212:369-383
Vieira AT, Macia L, Galvão I, Martins FS, Canesso MC, Amaral FA, Garcia CC, Maslowski KM, De Leon E, Shim D, Nicoli JR, Harper JL, Teixeira MM, Mackay CR. A Role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. Arthritis Rheumatol. 2015;67:1646-1656.
Sellin ME, Maslowski KM, Maloy KJ, Hardt WD. Inflammasomes of the intestinal epithelium. Trends Immunol. 2015;36:442-450.
2014
Scott C, Bonner J, Min D, Boughton P, Stokes R, Cha KM, Walters SN, Maslowski K, Sierro F, Grey ST, Twigg S, McLennan S, Gunton JE. Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing. Am J Physiol Cell Physiol. 2014;307:C349-357.
Sellin ME, Müller AA, Felmy B, Dolowschiak T, Diard M, Tardivel A, Maslowski KM, Hardt WD. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe. 2014;16:237-248.
2013
Zaiss MM, Maslowski KM, Mosconi I, Guenat N, Marsland BJ, Harris NL. IL-1β suppresses innate IL-25 and IL-33 production and maintains helminth chronicity. PLoS Pathog. 2013;9:e1003531.
Michallet MC, Rota G, Maslowski K, Guarda G. Innate receptors for adaptive immunity. Curr Opin Microbiol. 2013;16:296-302.
2012
Macia L, Thorburn AN, Binge LC, Marino E, Rogers KE, Maslowski KM, Vieira AT, Kranich J, Mackay CR. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol Rev. 2012;245:164-176
2011
Kranich J, Maslowski KM, Mackay CR. Commensal flora and the regulation of inflammatory and autoimmune responses. Semin Immunol. 2011;23:139-145.
Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol. 2011;12:5-9.
2009
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282-1286.
Introduction
The recent development of liquid biopsies has opened up new directions for monitoring the progression of cancer and the formation of metastasis, bringing us one step closer to effective personalised therapies. Despite these remarkable breakthroughs, metastasis remains the leading cause of cancer-related deaths. Therefore, it is of great significance to investigate the biology of metastasis and identify the critical steps and factors that need to be targeted in order to successfully develop efficient anti-metastatic treatments.
Our work broadly aims to understand how metastasis is regulated by the circadian rhythm. We particularly focus on a very rare cancer cell population that escapes from the primary tumour and spreads throughout the body via the bloodstream to establish new tumours in different locations, named Circulating Tumour Cells (CTCs). We are interested in the circadian rhythm as it has an intriguing role during cancer development and progression. While several studies have shown that the disruption of the circadian rhythm and the resulting misalignment of sleep-wake cycles promote tumour growth, our recent ground-breaking discovery indicates that the metastatic spread of breast cancer occurs during sleep. To further explore how the circadian rhythm drives metastasis, we focus on in vivo mouse models and we employ cutting edge microfluidics and robotic technologies, genetic engineering, next generation sequencing and in vivo imaging systems. We also analyse blood samples from cancer patients to identify circadian rhythm-related molecular vulnerabilities that could be used for the development of novel therapies. Finally, we explore chronotherapy to develop new approaches to drug administration that could be beneficial to cancer patients.
Lab Report
Key Publications
Diamantopoulou Z, Gvozdenovic A, Aceto N. A new time dimension in the fight against metastasis. Trends Cell Biol. 2023;10.1016/j.tcb.2023.02.002.
Diamantopoulou Z, Castro-Giner F, Schwab FD, Foerster C, Saini M, Budinjas S, Strittmatter K, Krol I, Seifert B, Heinzelmann-Schwarz V, Kurzeder C, Rochlitz C, Vetter M, Weber WP, Aceto N. The metastatic spread of breast cancer accelerates during sleep. Nature. 2022;607:156-162.
Scheidmann MC, Castro-Giner F, Strittmatter K, Krol I, Paasinen-Sohns A, Scherrer R, Donato C, Gkountela S, Szczerba BM, Diamantopoulou Z, Muenst S, Vlajnic T, Kunz L, Vetter M, Rochlitz C, Taylor V, Giachino C, Schroeder T, Platt RJ, Aceto N. An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression. Cancer Res. 2022;82:681-694.
Diamantopoulou Z, Castro-Giner F, Aceto N. Circulating tumor cells: Ready for translation? J Exp Med. 2020;217.
Diamantopoulou Z, White G, Fadlullah MZH, Dreger M, Pickering K, Maltas J, Ashton G, MacLeod R, Baillie GS, Kouskoff V, Lacaud G, Murray GI, Sansom OJ, Hurlstone AFL, Malliri A. TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells. Cancer Cell. 2017;31:621-634.e626.
Biography
Education and Qualifications
2010: PhD, Cellular Biology University of Patras, Greece
2005: BSc, Biology, University of Patras, Greece
Appointments
2023-present: Beatson Research Fellow, CRUK Scotland Institute, Glasgow, UK
2021-2023: Senior Postdoctoral Marie Curie Fellow, Molecular Oncology Group, ETH, Zürich, Switzerland
2019-2021: Senior Postdoctoral Marie Curie Fellow, Cancer Metastasis Group, University of Basel, Switzerland
2018-2019: Senior Cell Biologist, Drug Discovery Unit, CRUK Manchester, UK
2013-2018: Postdoctoral Fellow, Cell Signalling Group, CRUK Manchester Institute, UK
2010-2012: Postdoctoral Fellow, Immupharma and Laboratoire CRRET,CNRS, Universite Paris-Est, France
Honours and Awards
2021 Marie Skłodowska-Curie Postdoctoral Fellowship
2018 The BACR Chris Marshall Prize for Cell Signalling
Recent Publications
2023
Diamantopoulou Z, Gvozdenovic A, Aceto N. A new time dimension in the fight against metastasis. Trends Cell Biol. 2023;10.1016/j.tcb.2023.02.002.
Ginn L, Maltas J, Baker MJ, Chaturvedi A, Wilson L, Guilbert R, Amaral FMR, Priest L, Mole H, Blackhall F, Diamantopoulou Z, Somervaille TCP, Hurlstone A, Malliri A. A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. Proc Natl Acad Sci U S A. 2023;120(40):e2300489120.
2022
Scheidmann MC, Castro-Giner F, Strittmatter K, Krol I, Paasinen-Sohns A, Scherrer R, Donato C, Gkountela S, Szczerba BM, Diamantopoulou Z, Muenst S, Vlajnic T, Kunz L, Vetter M, Rochlitz C, Taylor V, Giachino C, Schroeder T, Platt RJ, Aceto N. An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression. Cancer Res. 2022;82:681-694.
Diamantopoulou Z, Castro-Giner F, Schwab FD, Foerster C, Saini M, Budinjas S, Strittmatter K, Krol I, Seifert B, Heinzelmann-Schwarz V, Kurzeder C, Rochlitz C, Vetter M, Weber WP, Aceto N. The metastatic spread of breast cancer accelerates during sleep. Nature. 2022;607:156-162.
2020
Diamantopoulou Z, Castro-Giner F, Aceto N. Circulating tumor cells: Ready for translation? J Exp Med. 2020;217.
2018
Woroniuk A, Porter A, White G, Newman DT, Diamantopoulou Z, Waring T, Rooney C, Strathdee D, Marston DJ, Hahn KM, Sansom OJ, Zech T, Malliri A. STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nature Communications. 2018;9:2124.
Chatzileontiadou DSM, Tsika AC, Diamantopoulou Z, Delbé J, Badet J, Courty J, Skamnaki VT, Parmenopoulou V, Komiotis D, Hayes JM, Spyroulias GA, Leonidas DD. Evidence for Novel Action at the Cell-Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies. ChemMedChem. 2018;13:259-269.
2017
Diamantopoulou Z, White G, Fadlullah MZH, Dreger M, Pickering K, Maltas J, Ashton G, MacLeod R, Baillie GS, Kouskoff V, Lacaud G, Murray GI, Sansom OJ, Hurlstone AFL, Malliri A. TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells. Cancer Cell. 2017;31:621-634.e626.
Diamantopoulou Z, Gilles ME, Sader M, Cossutta M, Vallée B, Houppe C, Habert D, Brissault B, Leroy E, Maione F, Giraudo E, Destouches D, Penelle J, Courty J, Cascone I. Multivalent cationic pseudopeptide polyplexes as a tool for cancer therapy. Oncotarget. 2017;8:90108-90122.
2015
Whalley HJ, Porter AP, Diamantopoulou Z, White GRM, Castañeda-Saucedo E, Malliri A. Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation. Nature Communications. 2015;6:7437.
2012
Pappa EV, Zompra AA, Diamantopoulou Z, Spyranti Z, Pairas G, Lamari FN, Katsoris P, Spyroulias GA, Cordopatis P. Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies. Biopolymers. 2012;98:525-534.
Diamantopoulou Z, Kitsou P, Menashi S, Courty J, Katsoris P. Loss of receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ) promotes prostate cancer metastasis. J Biol Chem. 2012;287:40339-40349.
2011
Pappa EV, Zompra AA, Spyranti Z, Diamantopoulou Z, Pairas G, Lamari FN, Katsoris P, Spyroulias GA, Cordopatis P. Enzymatic stability, solution structure, and antiproliferative effect on prostate cancer cells of leuprolide and new gonadotropin-releasing hormone peptide analogs. Biopolymers. 2011;96:260-272.
2010
Diamantopoulou Z, Bermek O, Polykratis A, Hamma-Kourbali Y, Delbé J, Courty J, Katsoris P. A Pleiotrophin C-terminus peptide induces anti-cancer effects through RPTPβ/ζ. Molecular Cancer. 2010;9:224.
2007
Bermek O, Diamantopoulou Z, Polykratis A, Dos Santos C, Hamma-Kourbali Y, Burlina F, Delbé J, Chassaing G, Fernig DG, Katsoris P, Courty J. A basic peptide derived from the HARP C-terminus inhibits anchorage-independent growth of DU145 prostate cancer cells. Exp Cell Res. 2007;313:4041-4050.
Introduction
Complex and dynamic interactions between cancer cells and elements of the tumour microenvironment (TME) underlie tumour development and contribute to therapy resistance. Facilitated by multiplex imaging and spatial omics data, architectural features of the TME organisation associated with clinical outcomes have been characterised in various types of solid tumours. One example is immune exclusion, where T lymphocytes are spatially excluded from tumour nests, limiting the effectiveness of immune checkpoint blockade-based immunotherapy. How clinically relevant TME architecture develops dynamically and how altering cellular properties and behaviours can re-sculpt TME organisation in favour of therapy response is less well established. We aim to gain insight into the dynamic delineation of, and the mechanistic basis for, clinically relevant TME organisation.
We focus on developing computational methods to map spatial features of the TME and deconstruct principles underlying the TME organisation. We are interested in a variety of approaches, including:
- Mechanistic models and computer simulations to investigate dynamic delineation of the TME organisation, such as sculpting of tumour/stroma architecture and spatial distribution of immune cells
- Quantitative analysis of molecular and spatial tumour data to characterise architectural features of the TME organisation, such as cell communities and neighbourhoods
- Machine learning frameworks to infer cellular and molecular mechanisms underpinning characteristic TME architectures.
We collaborate closely with experimental and clinical research groups. In application of our computational methods to spatial and molecular data of various solid tumours, including colorectal and pancreatic cancers, our goals are to discover novel spatial TME features associated with clinical outcomes and to identify cellular and molecular mechanisms for re-sculpting TME organisation in favour of therapy response and tumour elimination.
Lab Report
Key Publications
Fu^ X, Sahai E, Wilkins^ A. Application of digital pathology-based advanced analytics of tumour microenvironment organisation to predict prognosis and therapeutic response. The Journal of Pathology.2023;
Fu X*, Zhao Y,* Lopez JI, Rowan A, Au L, Fendler A, Hazell S, Xu H, Horswell S, Shepherd STC, Spencer CE, Spain L, Byrne F, Stamp G, O'Brien T, Nicol D, Augustine M, Chandra A, Rudman S, Toncheva A, Furness AJS, Pickering L, Kumar S, Koh DM, Messiou C, Dafydd DA, Orton MR, Doran SJ, Larkin J, Swanton C, Sahai E, Litchfield K, Turajlic S, Bates PA. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study. Nat Ecol Evol. 2022;6:88-102.
Zhao Y*, Fu X*, Lopez JI*, Rowan A, Au L, Fendler A, Hazell S, Xu H, Horswell S, Shepherd STC, Spain L, Byrne F, Stamp G, O'Brien T, Nicol D, Augustine M, Chandra A, Rudman S, Toncheva A, Pickering L, Sahai E, Larkin J, Bates PA, Swanton C, Turajlic S, Litchfield K. Selection of metastasis competent subclones in the tumour interior. Nat Ecol Evol. 2021;5:1033-1045.
*co-first authorship
^co-corresponding authorship
Biography
Education and Qualifications
2017: PhD, Biological Physics, Indiana University, Bloomington, USA
2012: BSc, Physics, Nanjing University, Jiangsu, China
Appointments
2023-present: Beatson Research Fellow, CRUK Scotland Institute, Glasgow, UK
2017-2023: Postdoctoral Researcher, Francis Crick Institute, UK
Awards and Fellowships
2022 Prostate Cancer Research grant, co-led by Erik Sahai and Anna Wilkins
2012 Eli Lilly Fellowships in Biocomplexity, Indiana University Bloomington, Indiana, USA
2008 People’s Scholarship, Nanjing University, Nanjing, China
Recent Publications
2023
Clarence T, Robert NSM, Sarigol F, Fu X, Bates PA, Simakov O. Robust 3D modeling reveals spatiosyntenic properties of animal genomes. iScience. 2023;26:106136.
Kato T, Jenkins RP, Derzsi S, Tozluoglu M, Rullan A, Hooper S, Chaleil RAG, Joyce H, Fu X, Thavaraj S, Bates PA, Sahai E. Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma. Elife. 2023;12.
Fu X, Sahai E, Wilkins A. Application of digital pathology-based advanced analytics of tumour microenvironment organisation to predict prognosis and therapeutic response. The Journal of Pathology.2023;
2022
Schmidbaur H, Kawaguchi A, Clarence T, Fu X, Hoang OP, Zimmermann B, Ritschard EA, Weissenbacher A, Foster JS, Nyholm SV, Bates PA, Albertin CB, Tanaka E, Simakov O. Emergence of novel cephalopod gene regulation and expression through large-scale genome reorganization. Nat Commun. 2022;13:2172.
Fu X, Zhao Y, Lopez JI, Rowan A, Au L, Fendler A, Hazell S, Xu H, Horswell S, Shepherd STC, Spencer CE, Spain L, Byrne F, Stamp G, O'Brien T, Nicol D, Augustine M, Chandra A, Rudman S, Toncheva A, Furness AJS, Pickering L, Kumar S, Koh DM, Messiou C, Dafydd DA, Orton MR, Doran SJ, Larkin J, Swanton C, Sahai E, Litchfield K, Turajlic S, Bates PA. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study. Nat Ecol Evol. 2022;6:88-102.
Fu X, Bates PA. Application of deep learning methods: From molecular modelling to patient classification. Exp Cell Res. 2022;418:113278.
2021
Zhao Y, Fu X, Lopez JI, Rowan A, Au L, Fendler A, Hazell S, Xu H, Horswell S, Shepherd STC, Spain L, Byrne F, Stamp G, O'Brien T, Nicol D, Augustine M, Chandra A, Rudman S, Toncheva A, Pickering L, Sahai E, Larkin J, Bates PA, Swanton C, Turajlic S, Litchfield K. Selection of metastasis competent subclones in the tumour interior. Nat Ecol Evol. 2021;5:1033-1045.
Muffoletto M, Qureshi A, Zeidan A, Muizniece L, Fu X, Zhao J, Roy A, Bates PA, Aslanidi O. Toward Patient-Specific Prediction of Ablation Strategies for Atrial Fibrillation Using Deep Learning. Front Physiol. 2021;12:674106.
Gerguri T, Fu X, Kakui Y, Khatri BS, Barrington C, Bates PA, Uhlmann F. Comparison of loop extrusion and diffusion capture as mitotic chromosome formation pathways in fission yeast. Nucleic Acids Res. 2021;49:1294-1312.
2020
Kakui Y, Barrington C, Barry DJ, Gerguri T, Fu X, Bates PA, Khatri BS, Uhlmann F. Fission yeast condensin contributes to interphase chromatin organization and prevents transcription-coupled DNA damage. Genome Biol. 2020;21:272.
Adhyapok P, Fu X, Sluka JP, Clendenon SG, Sluka VD, Wang Z, Dunn K, Klaunig JE, Glazier JA. A computational model of liver tissue damage and repair. PLoS One. 2020;15:e0243451.
2019
Muffoletto M, Fu X, Roy A, Varela M, Bates PA, Aslanidi OV. Development of a Deep Learning Method to Predict Optimal Ablation Patterns for Atrial Fibrillation. Paper presented at: 2019 IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB); 9-11 July 2019, 2019.
Clendenon SG, Fu X, Von Hoene RA, Clendenon JL, Sluka JP, Winfree S, Mang H, Martinez M, Filson AJ, Klaunig JE, Glazier JA, Dunn KW. A simple automated method for continuous fieldwise measurement of microvascular hemodynamics. Microvasc Res. 2019;123:7-13.
Clendenon SG, Fu X, Von Hoene RA, Clendenon JL, Sluka JP, Winfree S, Mang H, Martinez M, Filson A, Klaunig JE, Glazier JA, Dunn KW. Spatial Temporal Analysis of Fieldwise Flow in Microvasculature. J Vis Exp. 2019;10.3791/60493.
2018
Fu X, Sluka JP, Clendenon SG, Dunn KW, Wang Z, Klaunig JE, Glazier JA. Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models. PLoS One. 2018;13:e0198060.
2016
Fu X, Gens JS, Glazier JA, Burns S, Gast TJ. An Explanatory Computational Simulation of Contiguous Capillary Occlusion in Diabetic Retinopathy based on Patient-derived Vasculature. The FASEB Journal. 2016;30:555.551-555.551
Fu X, Sluka JP, Clendenon S, Glazier JA, Wang Z, Klaunig J, Ryan J, Dunn K. An in-Silico Model of Xenobiotic Distribution and Metabolism in a Simulated Mouse Hepatic Lobule. The FASEB Journal. 2016;30:1036.1038-1036.1038.
Sluka JP, Fu X, Swat M, Belmonte JM, Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA. A Liver-Centric Multiscale Modeling Framework for Xenobiotics. PLoS One. 2016;11:e0162428.
Gast TJ, Fu X, Gens JS, Glazier JA. A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion. J Diabetes Res. 2016;2016:2508381.
Fu X, Gens JS, Glazier JA, Burns SA, Gast TJ. Progression of Diabetic Capillary Occlusion: A Model. PLoS Comput Biol. 2016;12:e1004932.
