Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell–cell junctions, cell–matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.

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The tumor ascites environment is enriched with cytokines and growth factors especially members of the Transforming Growth Factor-β (TGF-β) family, that play crucial roles in modulating anoikis sensitivity and consequently metastatic progression in ovarian cancer. Here, we demonstrated for the first-time significant broad dichotomy between these TGF-β members: BMPs and TGF-β/activin and their regulated SMADs in this process. We previously reported BMP9/GDF2 to be in low to undetected levels in ovarian cancer patient-derived ascites and promoted anoikis resistance in both breast and ovarian cancer cell lines. We have now identified additional BMPs -BMP2, BMP4 and BMP9 as promoting anoikis sensitivity in a spectrum of ovarian cancer cells. Conversely, we found TGF-βs (1 and 2) to be in much higher expression and demonstrated that TGF-β and activin promoted anoikis resistance in ovarian cancer. Hence, in an attempt to identify genes downstream of BMPs that may provide anoikis resistance, transcriptomics was performed leading to the identification of Sox2, a developmental gene with prior established roles in OVCA, as being significantly downregulated in response to BMP9. We further uncovered Sox2 to be reciprocally regulated by anoikis-promoting BMPs (2, 4 and 9) and anoikis suppressing TGF-β and activin A. Our findings highlight a novel contrasting SMAD dependent regulation of Sox2 as a central node for controlling tumor cell survival in ovarian cancers demonstrating a subset of BMPs as a therapeutic strategy in cancer. The studies presented here begin to elucidate the mechanisms of reciprocal epigenetic regulation of Sox2 by BMP and TGF-β/activin in the context of ovarian cancer, which is the most lethal gynecologic malignancy in women due to peritoneal metastatic spread. Citation Format: Zainab M. Shonibare, Mehri Monavarian, Kathleen O'Connell, Diego Altamore, Abigail Shelton, Shubham Mehta, Renata Jaskula-Sztul, Rebecca Phaeton, Andrew Berchuck, Andrew B. Nixon, Rebecca Arend, Nam Y. Lee, Ryan Miller, Nadine Hempel, Karthikeyan Mythreye. Reciprocal Sox2 regulation by SMAD1 and SMAD3 is critical for anoikis resistance and metastasis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 107.