Ovarian carcinosarcoma genomics and pre-clinical models highlight the N-MYC pathway as a key driver and susceptibility to EMT-targeting therapy

Abstract

Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory from a single progenitor, resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). We show OCS from 18 women to be monoclonal through analysis of DNA variants from isolated carcinoma and sarcoma components. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure ovarian carcinomas, supporting the conversion theory. We used pre-clinical OCS models to test the efficacy of microtubule-targeting drugs, including eribulin, which has been shown to reverse EMT characteristics. We demonstrated that microtubule inhibitors, vinorelbine and eribulin, were more effective than standard-of-care platinum-based chemotherapy. Eribulin reduced mesenchymal characteristics, N-MYC expression and cholesterol biosynthesis. Finally, eribulin induced a strong immune response, supporting immunotherapy combinations in the clinic.

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…Carcinosarcomas (CS) are cancers which possess both carcinomatous and sarcomatous features but arise from a single progenitor [ 86 ]. In a few cases, the sarcomatous component is said to arise from the carcinomatous components through the process of EMT [ 87 ]. Carcinosarcomas have been observed mostly in female reproductive organs—uterus and ovaries.…”

“…Moreover, the level of ZEB1 was higher in the sarcomatous region when compared to the transitional region [ 93 ]. Similar to UCS, ovarian carcinosarcoma (OCS) showed enriched expression of EMT markers when compared to the cohort of high-grade serous carcinoma in TCGA [ 87 ], suggesting that OCS indicates phenotypic and/or lineage plasticity signatures through the EMT landscape.…”