Differential growth factor pathways in mesothelioma subtypes

Prof Daniel J. Murphy and Dr Luke Boulter

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Labs:
Murphy Group
Boulter Group
Duration: 4 years from September 2022
Closing Date: 27th May 2022

About us

Applications are invited from outstanding candidates to join a Cancer Research UK funded PhD programme at the Beatson Institute. These are funded by the Cancer Research UK Scotland Centre, a joint initiative between Edinburgh and Glasgow which brings together cancer scientists and clinicians from across the Universities of Edinburgh and Glasgow, delivering outstanding cancer research and improved patient care. The Cancer Research UK PhD programme is integrated into the research activities of the Centre with over 80 principal investigators contributing to this cross-disciplinary programme spanning from fundamental science to translational research. Research projects benefit from state-of-the art facilities for genomics, mass spectrometry, advanced microscopy, single cell technologies, and from advanced computational and informatics capabilities.

Project Description

The genetic landscape of Mesothelioma is dominated by loss of function mutations in various tumour suppressor genes (eg. CDKN2A/B; BAP1; NF2; Tp53), while mutations in dominant oncogenes common in other solid tumours (eg. EGFR; KRAS; CTNNB1) are extremely rare. It is not immediately clear how loss of the various tumour suppressors drives ectopic mesothelioma cell proliferation or otherwise sustains tumour phenotypes.

Using whole transcriptome analysis of genetically defined mesothelioma in mice, we have found that tumours presenting with distinct morphological features (ie. epithelioid versus sarcomatoid histology) exhibit sharply distinct gene expression profiles that implicate distinct mitogenic signalling cascades in sustaining tumour growth: Epithelioid tumours strongly express ligands, receptors and downstream intracellular transducers of the EGFR and WNT signalling cascades, whereas non-epithelioid tumours express high levels of MET ligand, along with elevated expression of Notch and Hedgehog signalling components. Importantly, these same signalling cascades are strongly conserved across species and their aberrant expression is reported in human mesothelioma (Bueno et al. '16; Hmeljak et al. '18; Nastase et al., '21). However, it is unclear from the data to date if the source of these growth factors is autocrine or if they are produced, perhaps initially, by the asbestos-inflamed microenvironment. Either way, these aberrantly regulated pathways may present new tumour vulnerabilities for stratified treatment of mesothelioma.

Project Aims

1) To disease-position our suite of GE mouse models against the subtypes of human mesothelioma (ongoing)

2) To systematically investigate the requirement for differential signalling cascades to support proliferation and/or viability of distinct mesothelioma subtypes in vitro and in vivo

3) To determine the source of growth factor production, timing of onset, and any relationship with defined TSG mutation combinations

4) To evaluate the pre-clinical therapeutic potential of targeted suppression of these cascades in appropriately disease-positioned mouse models of early-stage (ie. pre-malignant) and established mesothelioma

Application Procedure

Up to 3 studentships are available to start in September 2022 for outstanding applicants with a stipend of £19,000 p/a. These are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students will be registered for their degree in either Glasgow or Edinburgh, depending on the project they apply for.

We are looking for students with a very good degree in a Life Sciences subject and an aptitude for experimental work, who are also highly committed to pursuing a PhD and a career in cancer research. You should hold at least an upper second-class degree in a relevant subject and comply with English language requirements.

All applications will be administered centrally via the University of Edinburgh, please apply on the link below - this includes Glasgow-based projects with Glasgow-based supervisors: https://www.star.euclid.ed.ac.uk/public/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=PRPHDCECRC1F&code2=0020

Closing date: 27 May 2022

Interviews are expected to be held week beginning 27 June.

Applications are open to all individuals irrespective of nationality or country of residence.

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