Prof Sara Zanivan - Tumour Microenvironment and Proteomics

Introduction

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Current Vacancies:

Postdoctoral Research Scientist

Bioinformatician - Prof Sara Zanivan

Discovery Research

Cancer associated fibroblasts (CAFs) have emerged as a promising therapeutic target in cancer because it is now well established that they actively contribute to tumour pathology. CAFs are a unique cell type in that they are highly secretory, and their secretome dictates the structure of a tumour and influences the behaviour of cancer cells and other cell types.
With our research we want to understand the molecular mechanisms through which CAFs alter the tumour microenvironment (TME) to influence cancer aggressiveness and resistance to therapy.

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High-grade serous ovarian cancer and triple negative breast cancer are the major focus of our research because there are limited therapies against the cancer cells of these tumour types. However, CAFs are highly abundant in these tumours, and our overarching goal is to find ways to target CAFs in combination with other anti-cancer therapies to improve survival of cancer patients.

In the last few years, our work has described unprecedented ways through which CAFs create a TME that supports tumour invasion and metastasis by altering the structure of the extracellular matrix (ECM), and tumour blood vessels' and cancer cells' functions. A major focus of our on-going research is the metabolism of CAFs. We have found that cell metabolism is a major epigenetic regulator of CAF functions and that it can influence the translation of pro-tumorigenic ECM proteins. Our on-going research aims to investigate these aspects further and to understand how targeting specific metabolic pathways affects the composition and structure of the ECM and the immune-TME, and whether it can be exploited to halt cancer progression and improve effectiveness of conventional therapeutic treatments.

Our research is unique in that we mostly work with patient-derived cells that we generate in the lab from tissues that patients kindly donate to research. We also work with pre-clinical models relevant for ovarian and breast cancer. Moreover, because of our established expertise in mass spectrometry (MS)-proteomics, we develop tailored technology to study CAF biology, including their crosstalk signalling with other cell types in co-cultures in vitro and their metabolism in vivo.

Clinical Research

Recently, we have joined the effort to improve early detection of cancer in patients, since detecting cancer at an early stage can dramatically increase opportunities for curative intervention. To tackle this challenge, we are developing novel MS proteomic-based technology for biomarker discovery in body fluids. This research is funded by the CRUK Early Detection and Diagnosis Research scheme.

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This research is funded by the Stand Up to Cancer campaign for Cancer Research UK

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Lab Report

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Key Publications

Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, Juin A, Ismail S, Bryant DM, Markert EK, Machesky LM, Mazzone M, Sansom OJ, Zanivan S. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science signaling 2019; 12: eaan8247

van der Reest J, Lilla S, Zheng L*, Zanivan S*, Gottlieb E*. Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress. Nat Commun. 2018; 9: 1581

Hernandez-Fernaud JR, Ruengeler E, Casazza A, Neilson LJ, Pulleine E, Santi A, Ismail S, Lilla S, Dhayade S, MacPherson IR, McNeish I, Ennis D, Ali H, Kugeratski FG, Al Khamici H, van den Biggelaar M, van den Berghe PV, Cloix C, McDonald L, Millan D et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun 2017; 8: 14206

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J. 2017; 36: 2373-89

Biography

Education and qualifications

2006: PhD, Complex Systems Applied to Post Genomic Biology, University of Torino, Italy
2002: Master in Bioinformatics, University of Torino, Italy
2001: MS in Biology, University of Torino, Italy

Appointments

2010-present: Group Leader, CRUK Beatson Institute
2014-present Head of Proteomics Advanced Technology, CRUK Beatson Institute
2007-2010: Postdoctoral Fellow with Matthias Mann, Max Planck Institute of Biochemistry, Martinsried, Germany
2002-2006: PhD Student with Guido Serini and Federico Bussolino, Candiolo Cancer Institute IRCCS, Torino, Italy

Recent Publications

2022

Baudot AD, Wang VM, Leach JD, O'Prey J, Long JS, Paulus-Hock V, Lilla S, Thomson DM, Greenhorn J, Ghaffar F, Nixon C, Helfrich MH, Strathdee D, Pratt J, Marchesi F, Zanivan S, Ryan KM. Glycan degradation promotes macroautophagy. Proc Natl Acad Sci U S A. 2022;119(26):e2111506119.

Blomme A, Peter C, Mui E, Rodriguez Blanco G, An N, Mason LM, Jamieson LE, McGregor GH, Lilla S, Ntala C, Patel R, Thiry M, Kung SHY, Leclercq M, Ford CA, Rushworth LK, McGarry DJ, Mason S, Repiscak P, Nixon C, Salji MJ, Markert E, MacKay GM, Kamphorst JJ, Graham D, Faulds K, Fazli L, Gleave ME, Avezov E, Edwards J, Yin H, Sumpton D, Blyth K, Close P, Murphy DJ, Zanivan S, Leung HY. THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer. EMBO Molecular Medicine. 2022;

Kay EJ, Paterson K, Riero-Domingo C, Sumpton D, Däbritz JHM, Tardito S, Boldrini C, Hernandez-Fernaud JR, Athineos D, Dhayade S, Stepanova E, Gjerga E, Neilson LJ, Lilla S, Hedley A, Koulouras G, McGregor G, Jamieson C, Johson RM, Park M, Kirschner K, Miller C, Kamphorst JJ, Loayza-Puch F, Saez-Rodriguez J, Mazzone M, Blyth K, Zagoni M, Zanivan S. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature Metabolism. 2022;4(6):693-710.

Närvä E, Taskinen ME, Lilla S, Isomursu A, Pietilä M, Weltner J, Isola J, Sihto H, Joensuu H, Zanivan S, Norman J, Ivaska J. MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels. iScience. 2022;25:104459.

Salji MJ, Blomme A, Däbritz JHM, Repiscak P, Lilla S, Patel R, Sumpton D, van den Broek NJF, Daly R, Zanivan S, Leung HY. Multi-omics & pathway analysis identify potential roles for tumor N-acetyl aspartate accumulation in murine models of castration-resistant prostate cancer. iScience. 2022;25:104056.

Kay EJ, Zanivan S. Methylmalonic acid: an age-related metabolite that drives tumour aggressiveness. Nat Metab. 2022

2021

Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Sibbet GJ, Sumpton D, Zanivan S, Hedley A, Clark W, Huang DT. E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis. Oncogene. 2021;40(12):2149-2164.

Budden T, Gaudy-Marqueste C, Porter A, Kay E, Gurung S, Earnshaw CH, Roeck K, Craig S, Traves V, Krutmann J, Muller P, Motta L, Zanivan S, Malliri A, Furney SJ, Nagore E, Virós A. Ultraviolet light-induced collagen degradation inhibits melanoma invasion. Nat Commun. 2021;12:2742.

Gillen SL, Giacomelli C, Hodge K, Zanivan S, Bushell M, Wilczynska A. Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization. Genome Biol. 2021;22:284.

Kugeratski FG, Hodge K, Lilla S, McAndrews KM, Zhou X, Hwang RF, Zanivan S, Kalluri R. Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker. Nat Cell Biol. 2021;23(6):631-641.

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.

Marco S, Neilson M, Moore M, Perez-Garcia A, Hall H, Mitchell L, Lilla S, Blanco GR, Hedley A, Zanivan S, Norman JC. Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion. Nat Commun. 2021 Nov 24;12(1):6829.

Martinez RS, Salji MJ, Rushworth L, Ntala C, Rodriguez Blanco G, Hedley A, Clark W, Peixoto P, Hervouet E, Renaude E, Kung SHY, Galbraith LCA, Nixon C, Lilla S, Mackay GM, Fazli L, Gaughan L, Sumpton D, Gleave ME, Zanivan S, Blomme A, Leung HY. SLFN5 regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer. Cancer Res. 2021;81: 3664–78

Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, Bryant DM. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nat Commun. 2021;12:1623.

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.

Domen A, Quatannens D, Zanivan S, Deben C, Van Audenaerde J, Smits E, Wouters A, Lardon F, Roeyen G, Verhoeven Y, Janssens A, Vandamme T, van Dam P, Peeters M, Prenen H. Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer. Cancers (Basel). 2021;13(5).

Kay EJ, Koulouras G, Zanivan S. Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis. Front Oncol. 2021;11:719922.

Kay EJ, Zanivan S. Metabolic pathways fuelling protumourigenic cancer-associated fibroblast functions. Current Opinion in Systems Biology. 2021;28:100377.

Kay EJ, Zanivan S. Two opposing sub-populations of fibroblasts decide progression of pancreatic cancer. Cancer Cell. 2021; 39:1175-1177.

Paterson K, Zanivan S, Glasspool R, Coffelt SB, Zagnoni M. Microfluidic technologies for immunotherapy studies on solid tumours. Lab Chip. 2021;21:2306-2329.

2020

Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Chatrin C, Sibbet GJ, Zanivan S, Huang DT. DELTEX2 C-terminal domain recognizes and recruits ADP-ribosylated proteins for ubiquitination. Science Advances. 2020;6(34):eabc0629.

Blomme A, Ford CA, Mui E, Patel R, Ntala C, Jamieson LE, Planque M, McGregor GH, Peixoto P, Hervouet E, Nixon C, Salji M, Gaughan L, Markert E, Repiscak P, Sumpton D, Rodriguez Blanco G, Lilla S, Kamphorst JJ, Graham D, Faulds K, MacKay GM, Fendt S-M, Zanivan S, Leung HY. 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nat Commun. 2020; 11: 2508

Cao X, Lilla S, Cao Z, Pringle MA, Oka OBV, Robinson PJ, Szmaja T, van Lith M, Zanivan S, Bulleid NJ. The mammalian cytosolic thioredoxin reductase pathway acts via a membrane protein to reduce ER-localised proteins. Journal of cell science. 2020;

Lobo MJ, Reverte-Salisa L, Chao YC, Koschinski A, Gesellchen F, Subramaniam G, Jiang H, Pace S, Larcom N, Paolocci E, Pfeifer A, Zanivan S, Zaccolo M. Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy. Commun Biol. 2020;3(1):596.

Loveridge CJ, Slater S, Campbell KJ, Nam NA, Knight J, Ahmad I, Hedley A, Lilla S, Repiscak P, Patel R, Salji M, Fleming J, Mitchell L, Nixon C, Strathdee D, Neilson M, Ntala C, Bryson S, Zanivan S, Edwards J, Robson CN, Goodyear CS, Blyth K, Leung HY. BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration. Oncogene. 2020; 39: 1797–1806

Oizel K, Tait-Mulder J, Fernandez-de-Cossio-Diaz J, Pietzke M, Brunton H, Lilla S, Dhayade S, Athineos D, Blanco GR, Sumpton D, Mackay GM, Blyth K, Zanivan SR, Meiser J, Vazquez A. Formate induces a metabolic switch in nucleotide and energy metabolism. Cell death & disease. 2020;11:310.

Tait-Mulder J, Hodge K, Sumpton D, Zanivan S, Vazquez A. The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis. Cancer & Metabolism. 2020;8(1):20.

Taskinen ME, Närvä E, Conway JRW, Hinojosa LS, Lilla S, Mai A, De Franceschi N, Elo LL, Grosse R, Zanivan S, Norman JC, Ivaska J. MASTL promotes cell contractility and motility through kinase-independent signaling. J Cell Biol. 2020; 219.

Unbekandt M, Lilla S, Zanivan S, Olson MF. The CDC42 effector protein MRCKβ autophosphorylates on Threonine 1108. Small GTPases. 2020;11(6):451-460.

2019

Ferraro DA, Patella F, Zanivan S, Donato C, Aceto N, Giannotta M, Dejana E, Diepenbruck M, Christofori G, Buess M. Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells. BMC Cancer. 2019; 19: 312.

Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, Juin A, Ismail S, Bryant DM, Markert EK, Machesky LM, Mazzone M, Sansom OJ, Zanivan S. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science signaling 2019; 12: eaan8247.

Whitelaw JA, Lilla S, Paul NR, Fort L, Zanivan S, Machesky LM. CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors. Communicative & integrative biology. 2019;12:112-118.

Wilczynska A, Gillen SL, Schmidt T, Meijer HA, Jukes-Jones R, Langlais C, Kopra K, Lu WT, Godfrey JD, Hawley BR, 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 Biol. 2019; 20: 262.

2018

Dandoulaki M, Petsalaki E, Sumpton D, Zanivan S, Zachos G. Src activation by Chk1 promotes actin patch formation and prevents chromatin bridge breakage in cytokinesis. J Cell Biol 2018; 217: 3071–3089

Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, Lilla S, Neilson MP, Tafelmeyer P, Zanivan S, Ismail S, Bryant DM, Tomkinson NCO, Chamberlain LH, Mastick GS, Insall RH, Machesky LM. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol. 2018 ; 20: 1159-71.

Kugeratski FG, Batista M, Lima CVP, Neilson LJ, da Cunha ES, de Godoy LM, Zanivan S, Krieger MA, Marchini FK. Mitogen-Activated Protein Kinase Kinase 5 Regulates Proliferation and Biosynthetic Processes in Procyclic Forms of Trypanosoma brucei. J Proteome Res 2018; 17: 108-18.

Novo D, Heath N, Mitchell L, Caligiuri G, MacFarlane A, Reijmer D, Charlton L, Knight J, Calka M, McGhee E, Dornier E, Sumpton D, Mason S, Echard A, Klinkert K, et al. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat Commun 2018; 9: 5069.

Port J, Muthalagu N, Raja M, Ceteci F, Monteverde T, Kruspig B, Hedley A, Kalna G, Lilla S, Neilson L, Brucoli M, Gyuraszova K, Tait-Mulder J, Mezna M, Svambaryte S, et al. Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress. Cancer Discov 2018;8(5):632-47. doi: 10.1158/2159-8290.CD-17-0533
 
van der Reest J, Lilla S, Zheng L, Zanivan S, Gottlieb E. Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress. Nat Commun 2018; 9: 1581.

Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 2018; 18: e1700167.

2017

Diaz-Vera J, Palmer S, Hernandez-Fernaud JR, Dornier E, Mitchell LE, Macpherson I, Edwards J, Zanivan S, Norman JC. A proteomic approach to identify endosomal cargoes controlling cancer invasiveness. J Cell Sci 2017; 130: 697-711

Hernandez-Fernaud JR, Ruengeler E, Casazza A, Neilson LJ, Pulleine E, Santi A, Ismail S, Lilla S, Dhayade S, MacPherson IR, McNeish I, Ennis D, Ali H, Kugeratski FG, Al Khamici H, van den Biggelaar M, van den Berghe PV, Cloix C, McDonald L, Millan D et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun 2017; 8: 14206

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO 2017;  36: 2373-89

van den Eshof BL, Hoogendijk AJ, Simpson PJ, van Alphen FPJ, Zanivan S, Mertens K, Meijer AB, van den Biggelaar M. Paradigm of Biased PAR1 (Protease-Activated Receptor-1) Activation and Inhibition in Endothelial Cells Dissected by Phosphoproteomics. Arterioscler Thromb Vasc Biol 2017; 37: 1891-1902

Norman J, Zanivan S (2017) Chloride intracellular channel 3: A secreted pro-invasive oxidoreductase. Cell Cycle: 16; 1993-4

Reid SE, Zanivan S. Tumor stiffness extends its grip on the metastatic microenvironment. Mol Cell Oncol 2017; 4: e1372866

2016

Patella F, Neilson LJ, Athineos D, Erami Z, Anderson KI, Blyth K, Ryan KM, Zanivan S. In-Depth Proteomics Identifies a Role for Autophagy in Controlling Reactive Oxygen Species Mediated Endothelial Permeability. J Proteome Res. 2016; 15: 2187-97

Clarke CJ, Berg TJ, Birch J, Ennis D, Mitchell L, Cloix C, Campbell A, Sumpton D, Nixon C, Campbell K, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Jones JL, Haywood L, Pulleine E, Yin HB, Strathdee D, Sansom O, Blyth K, McNeish I, Zanivan S, Reynolds AR, Norman JC. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis. Curr Biol. 2016; 26: 755-65

Lab Members

Zanivan lab 2020 123

Postdoctoral Scientists

Samuel Atkinson
Emily Kay
Britt Sterken

Scientific Officers

Ulla-Maja Bailey
Lisa Neilson

Clinical Research Fellow

Douglas Cartwright

PhD Students

Teresa Glauner
Greg Koulouras
Ilaria Puoti

Former Lab Members

Fernanda Kugeratski (Post-doc, MD Anderson, USA)
Francesca Patella (Post-doc, University College London, UK)
Juan Ramon Hernandez (Manager Proteomic Facility, University of Warwick, UK)
Steven Reid (Post-doc, Lund University, SE)
Maartje van den Biggelaar (Scientist, Sanquin Research, Amsterdam, NL)

Research

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Seminars

Seminars 2021

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