Abstract 1042: Cellular plasticity and migratory modalities in high-grade serous ovarian carcinoma

Abstract

Abstract Epithelial-mesenchymal (E-M) switch associated plasticity is crucial for the gradual destabilization of tumor tissue architecture to facilitate metastasis. Several studies towards comprehension of the metastatic cascade employ an overview of the phenotype specific markers and their association with distinct functionalities of migration, invasion, stemness, anoikis resistance, ECM remodeling, etc. Recent work on the dissection of phenotypic transitions has identified the existence of transitionary intermediate states across multiple cancers which exhibit greater plasticity as compared to the two phenotypic extremes. In a previous study from our group, we successfully identified molecular subclasses in high grade serous ovarian carcinoma (HGSC) that were associated with distinct modes of metastatic dissemination viz., collective cell migration (CCM) and EMT. Towards, elucidating contributions of distinct phenotypic states to CCM and EMT along with a comprehension of associated molecular regulators we resolved a phenotypic spectrum along the E-M axis. Identification of five phenotypic states followed by their functional characterization was associated with differential migratory capabilities that were further dissected with the aid of live cell imaging to quantitatively distinguish CCM and EMT. Enhanced visual output and extraction of three quantitative metrics viz., displacement, velocity and nearest neighbours generated an informative tool for assessing migratory modes in vitro. Furthermore, these metrics identified migratory modalities inclusive of wound closure by proliferation (passive CCM), sheet-like cell migration (active CCM) and individual cell migration (EMT). Interestingly, phenotypic status and migratory modes across the spectrum emerged as a consequence of a balance between expression and differential sub-cellular localization of two transcription factors viz. Tcf21 and Slug. Application of the novel migratory analyses in view of chemotherapeutic challenges identified the emergence of an epithelial state across the spectrum facilitated by Tcf21 mediated Slug repression and resulted in a switch from EMT to aCCM-mediated migration. Our study thus provides a comprehensive dissection of the E-M axis in HGSC in view of associated functional attributes. Acknowledgements: DBT Indo-Finnish Collaborative Grants, DBT Indo-Australia Collaborative Grants and NCCS Intramural Grants to SAB funded this research. SSV received fellowship from CSIR. Citation Format: Sharmila A. Bapat, Sagar Varankar. Cellular plasticity and migratory modalities in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1042.