A Multistep Tumor Growth Model of High Grade Serous Ovarian Carcinoma Identifies Hypoxia Associated Signatures

Abstract

High-grade serous ovarian carcinoma (HGSC) is associated with late-stage disease presentation and poor prognosis, with limited understanding of early transformation events. Our study presents a comprehensive analysis of tumor progression and organ-specific metastatic dissemination to identify hypoxia-associated molecular, cellular, and histological alterations during HGSC tumor growth. H&E staining and subsequent histological assessment of tumor volume-based categories revealed recapitulation of numerous clinical features, including the prevalence of >0.0625≤0.5cm3 volume tumors and metastatic spread by orthotopic xenografts. The constant evolution of the tissue architecture concerning increased hyaluronic acid deposition, tumor vasculature, necrosis, altered proliferative potential, and gland forming ability of the tumor cells was identified. Flow cytometry and label chase-based molecular profiling across the tumor regenerative hierarchy identified the hypoxia-vasculogenic niche and the hybrid epithelial-mesenchymal tumor-cell state as determinants of self-renewal capabilities of progenitors and cancer stem cells (CSCs). A regulatory network and mathematical model based on tumor histology and molecular signatures predicted hypoxia-inducible factor 1-alpha (HIF1A) as a central node connecting epithelial-mesenchymal transition, metabolic and necrotic pathways in HGSC tumors. Thus, our findings provide a temporal resolution of hypoxia-associated events that sculpt HGSC tumor growth, and an in-depth understanding of it may aid in the early detection and treatment of HGSC.