Sara Zanivan - Tumour Microenvironment and Proteomics

Introduction

Zanivan Sara 032

The tumour stroma is composed of many different cell types and extracellular matrix components that work in concert to generate a microenvironment permissive to tumour initiation, progression and metastasis. Cancer associated fibroblasts (CAFs) are a major non-neoplastic cell type in solid tumours. They are characterised by the ability to secrete a plethora of factors and establish physical interactions with the surrounding cells, including endothelial, cancer and immune cells. This results in CAFs being key players in cancer pathology through creating an aberrant tumour microenvironment and altering the behaviour of the surrounding cells. For this reason, CAFs are considered a promising target for therapy.

Our research is focused on identifying how to exploit CAFs to effectively target tumours, primarily breast and ovarian cancers. In particular, we are studying the dynamic interactions that CAFs establish with cancer cells and endothelial cells to identify

  • CAF pathways fundamental to support their pro-invasive/tumourigenic functions,
  • CAF-endothelial cell interactions that promote blood vessel remodelling and metastasis, and
  • CAF-cancer cell interactions upon which cancer cells are critically vulnerable.

To achieve this, our group exploits and develops in vitro and in vivo models that we investigate using a unique combination of cell and molecular biology approaches, together with state-of-the-art quantitative mass spectrometry-based proteomics.

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

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 Apr 20;9(1):1581. doi: 10.1038/s41467-018-04003-3

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

Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, Maione F, Hernandez-Fernaud JR, Mackay G, Zheng L, Reid S, Frezza C, Giraudo E, Fiorio Pla A, Anderson K, Ruppin E, Gottlieb E, Zanivan S. Proteomics-based metabolic modelling reveals that fatty acid oxidation controls endothelial cell permeability. Mol Cell Proteomics 14: 621-34, 2015

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

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. doi: 10.1083/jcb.201802102

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 Oct; 20(10): 1159-71. doi: 10.1038/s41556-018-0198-9

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(1):108-18. doi: 10.1021/acs.jproteome.7b00415

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(1):1581. doi: 10.1038/s41467-018-04003-3

Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 2018;18(5-6):e1700167. doi: 10.1002/pmic.201700167

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

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. doi: 10.1021/acs.jproteome.7b00415. Epub 2017 Nov 7.

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; J 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 15: 2187-97, 2016

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 26: 755-65, 2016

2015

Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, Maione F, Hernandez-Fernaud JR, Mackay G, Zheng L, Reid S, Frezza C, Giraudo E, Fiorio Pla A, Anderson K, Ruppin E, Gottlieb E, Zanivan S. Proteomics-based metabolic modelling reveals that fatty acid oxidation controls endothelial cell permeability. Mol Cell Proteomics 14: 621-34, 2015

2014

Guo Z, Neilson LJ, Zhong H, Murray PS, Zanivan S, Zaidel-Bar R. E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Sci Signal 7: rs7, 2014

Reid S, Hernandez-Fernaud JR, Zanivan S. In vivo quantitative proteomics for the study of oncometabolism. Methods Enzymol 543: 235-59, 2014

van den Biggelaar M, Hernández-Fernaud JR, van den Eshof BL, Neilson LJ, Meijer AB, Mertens K, Zanivan S. Quantitative phosphoproteomics unveils temporal dynamics of thrombin signaling in human endothelial cells. Blood 123: e22-36, 2014

Lab Members

Zanivan lab R23 Sept 2018

Post-docs

Samuel Atkinson
David Mcgarry
Alice Santi

Principal Scientific Officer

Lisa Neilson

PhD Students

Emily Kay
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

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