ID8 cells manifest phenotypic plasticity and molecular heterogeneity of high-grade serous ovarian cancer in response to the local tissue niche.

Abstract

Spontaneously transformed mouse ovarian surface epithelial cell line ID8 generates a syngeneic mouse model, recapitulating the primary and metastatic stages of the malignancy hence, frequently used in pre-clinical evaluation. Due to inherent phenotypic plasticity, primary and metastatic tumors show contrasting phenotypic features dictated by the tissue niche. To address the tumor heterogeneity within the model we stratified it into a specific molecular subtype, which would provide an accurate setting for interpretation of experimental data. Stratification was performed on ID8 cell line and ID8 generated xenografts based on immunostaining, live cell imaging, histopathology, transcriptomics and proteomics. Tumor microenvironment (TME) investigation for each xenograft was done through flow cytometry analysis. ID8 cells present epithelial/mesenchymal (E/M) phenotype. Phenotypic plasticity retention in them causes class switching of ID8 cells in response to niche alteration, from E/M (in culture) to intermediate epithelial (iE) in orthotopic tumors while intermediate mesenchymal (iM) in subcutaneous tumors. Metastasis of ID8 primary tumor resulted into differentiated mesenchymal phenotype in ascites while differentiated epithelial phenotype in secondary intestinal tumors. Immune profiling of primary and secondary xenografts revealed differences in immune repertoire of tumors, highlighting subcutaneous tumor model to be inappropriate as compared to orthotopic model. Local tissue niche modulates the phenotype of tumors generated, transitioning through intermediate states towards a final commitment to either an epithelial or mesenchymal state that recapitulates the reported class switching in patient tumors. During disease progression, such heterogeneity of tumor cells at different niche(s) and their cross-talks with discrete TME at each site, will pose challenges for effective therapy.