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

Ho, GY; Kyran, EL; Bedo, J; Wakefield, MJ; Ennis, DP; Mirza, HB; Vandenberg, CJ; Lieschke, E; Farrell, A; Hadla, A; Lim, R; Dall, G; Vince, JE; Chua, NK; Kondrashova, O; Upstill-Goddard, R; Bailey, UM; Dowson, S; Roxburgh, P; Glasspool, RM; Bryson, G; Biankin, AV; Scottish Genomes Partnership; Cooke, SL; Ratnayake, G; McNally, O; Traficante, N; Australian Ovarian Cancer Study; DeFazio, A; Weroha, SJ; Bowtell, DD; McNeish, IA; Papenfuss, AT; Scott, CL; Barker, HE

Author(s): Ho, GY; Kyran, EL; Bedo, J; Wakefield, MJ; Ennis, DP; Mirza, HB; Vandenberg, CJ; Lieschke, E; Farrell, A; Hadla, A; Lim, R; Dall, G; Vince, JE; Chua, NK; Kondrashova, O; Upstill-Goddard, R; Bailey, UM; Dowson, S; Roxburgh, P; Glasspool, RM; Bryson, G; Biankin, AV; Scottish Genomes Partnership; Cooke, SL; Ratnayake, G; McNally, O; Traficante, N; Australian Ovarian Cancer Study; DeFazio, A; Weroha, SJ; Bowtell, DD; McNeish, IA; Papenfuss, AT; Scott, CL; Barker, HE;
Details: Publication Year 2022-12-02,Volume 82,Issue #23,Page 4457-4473
Journal Title: Cancer Research
Publication Type: Research article
Abstract: 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.
Keywords: Humans; Female; Epithelial-Mesenchymal Transition/genetics; *Ovarian Neoplasms/drug therapy/genetics/pathology; Cell Transformation, Neoplastic; *Antineoplastic Agents/pharmacology; Microtubules; *Carcinosarcoma/genetics/pathology; *Carcinoma
Department(s): Laboratory Research; Medical Oncology
PubMed ID: 36206301
Publisher's Version: https://doi.org/10.1158/0008-5472.CAN-21-4012
Open Access at Publisher's Site: https://doi.org/10.1158/0008-5472.Can-21-4012
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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