Dissecting tumour stroma heterogeneity in high grade serous ovarian cancer using cutting edge mass spectrometry proteomics approaches

Prof Sara Zanivan

Follow LINK to apply

APPLY HERE. Application closing date: 9 January 2022.

The High grade serous (HGS) ovarian cancer is the deadliest gynaecological cancer due to the limited availability of targeted therapies against the cancer cells, because only few targetable recurrent mutations have been identified in these cells. HGS ovarian tumours have an extensive cancer-associated fibroblast (CAF)-rich stroma that largely interact with cancer and immune cells. CAFs play fundamental roles in tumour malignancy. They have been shown to influence the phenotype of cancer and immune cells, as well as therapy resistance, and have emerged as an attractive alternative therapeutic target. However, what the molecular mechanisms behind these functions are, whether they are conserved at different metastatic sites, and whether they are targetable is still largely unclear. This project will start tackling these questions using cutting edge technologies and relevant HGS ovarian cancer patient samples.

The student will use laser-capture microdissection and state-of the art MS proteomics technologies to spatially assess the proteome of the stroma of HGS ovarian tumours. Data will be integrated with tumour features such as presence/absence of immune cells and proximity of cancer cells, to identify stromal signalling potentially involved in shaping cancer and immune cell behaviour important to support tumour malignancy and resistance to therapy. Metabolic pathways will be a major focus of the data analysis. Key findings will be functionally investigated with knock-out and over-expression techniques using patient-derived cells and relevant in vitro co-culture models already established in the Zanivan group. Final findings may be further validated in in vivo models.

Keywords: CAFs, Tumour microenvironment; Ovarian cancer; Proteomics; Mass Spectrometry

Publications:

Emily J Kay, Karla Paterson, David Sumpton, Ekaterina Stepanova, Claudia Boldrini, Juan R Hernandez-Fernaud, Sandeep Dhayade, Enio Gjerga, Robin Shaw, Lisa J Neilson, Grigorios Koulouras, Grace McGregor, Sergio Lilla, Craig Jamieson, Ann Hedley, Radia Marie Johnson, Morag Park, Crispin Miller, Jurre J Kamphorst, Fabricio Loayza-Puch, Julio Saez-Rodriguez, Karen Blyth, Michele Zagnoni, Sara Zanivan. Metabolic control of tumour extracellular matrix production in cancer-associated fibroblasts. BioRxiv https://doi.org/10.1101/2020.05.30.125237

Kay EJ, Zanivan S. Metabolic pathways fuelling protumourigenic cancer-associated fibroblast functions. Curr Opin Syst Biol. 2021Dec, 28.

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, and Zanivan S. Hypoxic cancer–associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science Signaling 2019 12(567), eaan8247. Cover Story. Editor's choice in Science Signaling 12(569), eaax0155.

van der Reest J , Lilla S, Zheng L*, Zanivan S* and Gottlieb E*. Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress. Nat Commun. 2018 9(1):1581. *Corresponding author.

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, Román-Fernández Á, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM, Salmeron-Sanchez M, Machesky LM, Carlin LM, Blyth K, Mazzone M, Zanivan S. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J. 2017 36(16):2373-2389.

For informal enquiries or further details on the project, please email Prof Sara Zanivan (sara.zanivan@glasgow.ac.uk).

APPLY HERE. Application closing date: 9 January 2022.

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