WEHI PhD Completion Seminar hosted by Professor Clare Scott

Anthony Hadla

PhD Student – Scott Laboratory, ACRF Cancer Biology & Stem Cells division, WEHI

Investigating epithelial-to-mesenchymal plasticity in ovarian carcinosarcoma preclinical models to identify potential targets for therapeutic intervention

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Lounge

Ovarian carcinosarcoma (OCS) is a rare and aggressive subtype of ovarian cancer characterised by the presence of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components. We and others have demonstrated that the sarcomatous component of these tumours arises through epithelial-to-mesenchymal plasticity (EMP), specifically the process of epithelial-to-mesenchymal transition (EMT). First-line platinum- and taxane-based chemotherapy shows limited efficacy in the clinic against OCS compared to high grade serous ovarian carcinoma (HGSOC), the most common type of ovarian cancer. As these tumours are associated with similar genetic aberrations, the unique sarcomatous component of OCS is predicted to be driving this disparity in treatment response.

Hybrid epithelial/mesenchymal (E/M) cells exist in OCS and many other cancers, where tumour cells acquire mesenchymal properties whilst maintaining expression of epithelial markers. These hybrid E/M cells have advantages in multiple facets of tumour progression, including tumorigenicity, immune evasion, metastasis, and drug resistance. Despite this, many attempts to reverse EMT in cancer have focused on targeting the highly drug-resistant mesenchymal cells, which often have limited contributions to metastasis. In fact, reversing EMT in these fully mesenchymal cells may transition them into the highly plastic and aggressive hybrid E/M state. Consequently, identifying markers of hybrid E/M cells for therapeutic targeting may be a more effective strategy for treating OCS.

In this study, we used single-cell RNA sequencing, spatial transcriptomics, cell surface proteomics, and flow cytometry to characterise an extensive cohort of OCS patient-derived xenograft models. From this, we were able to establish OCS-specific epithelial- and mesenchymal-like gene signatures not previously described in the literature. We also identified genetic elements and signalling pathways enriched within cells representing a hybrid E/M state that may drive the tumorigenic, metastatic, and drug-resistant characteristics of OCS. This presents a new strategy to target OCS and drive tumour cells towards a more epithelial and chemosensitive phenotype.

All welcome!