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

High-grade serous ovarian carcinoma (HGSC) is associated with late-stage disease presentation and poor prognosis, with a limited understanding of early transformation events. Our study analyzes HGSC tumor progression and organ-specific metastatic dissemination to identify hypoxia-associated molecular, cellular, and histological alterations. Clinical characteristics of the HGSC were replicated in orthotopic xenografts, which involve metastatic dissemination and the prevalence of group B tumors (volume: >0.0625 ≤ 0.5 cm3). Enhanced hyaluronic acid (HA) deposition, expanded tumor vasculature, and increased necrosis contributed to the remodeling of tumor tissue architecture. The proliferative potential of tumor cells and the ability to form glands were also altered during tumor growth. 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. 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 HA synthesis, epithelial-mesenchymal transition, metabolic, vasculogenic, inflammatory, and necrotic pathways in HGSC tumors. Thus, our findings provide a temporal resolution of hypoxia-associated events that sculpt HGSC tumor growth; an in-depth understanding of it may aid in the early detection and treatment of HGSC.