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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., (© 2022 S. Karger AG, Basel.)

Molecular stratification of high-grade serous ovarian carcinoma (HGSC) for targeted therapy is a pertinent approach in improving prognosis of this highly heterogeneous disease. Enabling the same necessitates identification of class-specific biomarkers and their robust detection in the clinic. We have earlier resolved three discrete molecular HGSC classes associated with distinct functional behavior based on their gene expression patterns, biological networks, and pathways. An important difference revealed was that Class 1 is likely to exhibit cooperative cell migration (CCM), Class 2 undergoes epithelial to mesenchymal transition (EMT), while Class 3 is possibly capable of both modes of migration. In the present study, we define clinical stratification of HGSC tumors through the establishment of standard operating procedures for immunohistochemistry and histochemistry based detection of a panel of biomarkers including TCF21, E-cadherin, PARP1, Slug, AnnexinA2, and hyaluronan. Further development and application of scoring guidelines based on expression of this panel in cell line-derived xenografts, commercial tissue microarrays, and patient tumors led to definitive stratification of samples. Biomarker expression was observed to vary significantly between primary and metastatic tumors suggesting class switching during disease progression. Another interesting feature in the study was of enhanced CCM-marker expression in tumors following disease progression and chemotherapy. These stratification principles and the new information thus generated is the first step towards class-specific personalized therapies in the disease.