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Contains fulltext : 283536.pdf (Publisher’s version ) (Closed access) The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Metastatic growth of ovarian cancer cells into the peritoneal cavity requires adaptation to various cellular stress factors to facilitate cell survival and growth. Here we demonstrate the role of PVT1, one such stress induced long non-coding RNA, in ovarian cancer growth and metastasis. PVT1 is an amplified and overexpressed lncRNA in ovarian cancer with strong predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by ovarian tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1 dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation models in vivo. We find that reducing PVT1 causes widespread transcriptome changes leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which directly impacts chemosensitivity. Together, these findings implicate PVT1 as a promising therapeutic target to suppress metastasis and avoid chemoresistance in ovarian cancer.SUMMARY BLURBPVT1 is a stress-responsive IncRNA regulated by YAP1, leading to increased ovarian cancer metastasis and chemoresistance, making PVT1 a promising therapeutic target.

SummaryGrowth factors in the tumor environment are key regulators of cell survival and metastasis. Here we reveal, dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin, and their downstream SMAD effectors. Gene expression profiling uncovered Sox2 as a key signaling node regulated in an opposing manner by anoikis-promoting BMP2, 4 and 9, and anoikis-suppressing TGF-β and activin A. We find that Sox2 repression by BMPs robustly inhibits intraperitoneal tumor burden and increases survival in multiple ovarian cancer models. Repression of Sox2 is driven by SMAD1 dependent histone H3K27me3 recruitment and DNA methylation at SOX2’s promoter. Conversely, TGF-β and activin A promote Sox2 expression, and anoikis resistance by SMAD3 mediated histone H3K4me3 recruitment. We find that balancing Sox2 levels is critical for anoikis, as transcriptomics reveals regulation of key cell death pathways. Moreover, BMP-driven SMAD1 signaling can override TGF-β and activin’s effect on Sox2, which has clinical significance due to the high levels of TGF-β we find in ovarian cancer patients. Together, our findings identify Sox2 as a contextual and contrastingly regulated key node, downstream of TGF-β superfamily members controlling anoikis and metastasis in ovarian cancers.HighlightsSox2 is a key node for anoikis resistance in cancerSox2 is differentially regulated by TGF-β/activin and BMPs in broad cancersBMP9 is a robust metastasis suppressor by lowering Sox2Sox2 regulation is contextual, epigenetic and at the transcriptional level

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.

OBJECTIVES/SPECIFIC AIMS: To understand the role of PGF2a and to characterize a novel cyclooxyrgenase (COX)-independent prostaglandin synthesis pathway in epithelial ovarian cancer. METHODS/STUDY POPULATION: We used high grade epithelial ovarian cancer cell line (OVCAR3) as a model to study our pathway. Our main mode of PGF2a detection is through mass spectrometry. RESULTS/ANTICIPATED RESULTS: Our current results suggest the OVCAR3 cells may synthesize PGF2a independently of COX enzymes. We anticipate this novel pathway may be dependent on the TGFb pathway. DISCUSSION/SIGNIFICANCE OF IMPACT: Understanding the role and synthesis pathway of PGF2a may allow us to uncover a novel therapeutic pathway for high grade ovarian cancer.