Prof John Le Quesne - Deep Phenotyping of Solid Tumours

Introduction

LeQuesne John

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:

  1. 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
  2. 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)
  3. 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

icon Le Quesne Lab Report

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

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 Nov 6. Online ahead of print.

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

Histopathology Technology Manager

Leah Officer-Jones

Postdoctoral Scientist

Ian Powley

Senior Scientific Officer

Silvia Cusuman 

Fiona Ballantyne

 

Research

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Seminars

Seminars 2021

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