Cancer Res. 2022 Oct 07. pii: CAN-21-4012. [Epub ahead of print]
Gwo-Yaw Ho,
Elizabeth L Kyran,
Justin Bedo,
Matthew J Wakefield,
Darren P Ennis,
Hasan B Mirza,
Cassandra J Vandenberg,
Elizabeth Lieschke,
Andrew Farrell,
Anthony Hadla,
Ratana Lim,
Genevieve Dall,
James E Vince,
Ngee Kiat Chua,
Olga Kondrashova,
Rosanna Upstill-Goddard,
Ulla-Maja Bailey,
Suzanne Dowson,
Patricia Roxburgh,
Rosalind M Glasspool,
Gareth Bryson,
Andrew V Biankin,
Susanna L Cooke,
Gayanie Ratnayake,
Orla McNally,
Nadia Traficante,
Anna DeFazio,
S John Weroha,
David D Bowtell,
Iain A McNeish,
Anthony T Papenfuss,
Clare L Scott,
Holly E Barker.
Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with 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). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes.