Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin

Ho, G.-Y. et al. (2022) Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin. Cancer Research, 82(23), pp. 4457-4473. (doi: 10.1158/0008-5472.can-21-4012) (PMID:36206301) (PMCID:PMC9716257)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bryson, Dr Gareth and Mcneish, Professor Iain and Glasspool, Dr Rosalind and Bailey, Dr Ulla-Maja and Ennis, Dr Darren and Roxburgh, Dr Patricia and Biankin, Professor Andrew and Dowson, Miss Suzanne
Authors: Ho, G.-Y., Kyran, E. L., Bedo, J., Wakefield, M. J., Ennis, D. P., Mirza, H. B., Vandenberg, C. J., Lieschke, E., Farrell, A., Hadla, A., Lim, R., Dall, G., Vince, J. E., Chua, N. K., Kondrashova, O., Upstill-Goddard, R., Bailey, U.-M., Dowson, S., Roxburgh, P., Glasspool, R. M., Bryson, G., Biankin, A. V., Cooke, S. L., Ratnayake, G., McNally, O., Traficante, N., DeFazio, A., Weroha, S. J., Bowtell, D. D., Mcneish, I. A., Papenfuss, A. T., Scott, C. L., and Barker, H. E.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research (AACR)
ISSN (Online):1538-7445
Published Online:07 October 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cancer Research 82(23):4457-4473
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190899Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1CS - Experimental Therapeutics