Prof Daniel J. Murphy and Dr Luke Boulter
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.
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