Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin.

Autor:	Ho GY; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; The Royal Women's Hospital, Parkville, Victoria, Australia., Kyran EL; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Cancer Research UK Cambridge Institute, Cambridge, United Kingdom., Bedo J; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; School of Computing and Information Systems, the University of Melbourne, Parkville, Victoria, Australia., Wakefield MJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia., Ennis DP; Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Mirza HB; Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Vandenberg CJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Lieschke E; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Farrell A; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Hadla A; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Lim R; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Dall G; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Vince JE; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Chua NK; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Kondrashova O; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Upstill-Goddard R; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Bailey UM; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Dowson S; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Roxburgh P; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom., Glasspool RM; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom., Bryson G; Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom., Biankin AV; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Cooke SL; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Ratnayake G; The Royal Women's Hospital, Parkville, Victoria, Australia., McNally O; The Royal Women's Hospital, Parkville, Victoria, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Traficante N; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., DeFazio A; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.; The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia., Weroha SJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota., Bowtell DD; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., McNeish IA; Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom., Papenfuss AT; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Scott CL; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; The Royal Women's Hospital, Parkville, Victoria, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Barker HE; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Dec 02; Vol. 82 (23), pp. 4457-4473.
DOI:	10.1158/0008-5472.CAN-21-4012
Abstrakt:	Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized 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 analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that 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 tumors. 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. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation 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 that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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