Mohit Kumar Jolly

Exploring the role of EMT in ovarian cancer progression using a multiscale mathematical model

Abstract Epithelial-to-mesenchymal transition (EMT) plays a key role in the progression of cancer tumours, significantly reducing the success of treatment. EMT occurs when a cell undergoes phenotypical changes, resulting in enhanced drug resistance, higher cell plasticity, and increased metastatic abilities. Here, we employ a 3D agent-based multiscale modelling framework using PhysiCell to explore the role of EMT over time in two cell lines, OVCAR-3 and SKOV-3. This approach allows us to investigate the spatiotemporal progression of ovarian cancer and the impacts of the conditions in the microenvironment. OVCAR-3 and SKOV-3 cell lines possess highly contrasting tumour layouts, allowing a wide range of different tumour dynamics and morphologies to be tested and studied. Along with performing sensitivity analysis on the model, simulation results capture the biological observations and trends seen in tumour growth and development, thus helping to obtain further insights into OVCAR-3 and SKOV-3 cell line dynamics.

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 cm<sup>3</sup>). 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.