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SOX9 is a driver of a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer [Unenriched_Tumor]

ABSTRACT: Resistance to platinum-based chemotherapies remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The complex and multifaceted nature of this cell state has been thought to originate in a small subpopulation of inherently resistant cancer stem cells (CSCs) in naïve tumors. However, there is increasing evidence that the chemoresistance state can be transiently acquired by non-stem cancer cells as well. Regardless of the route to chemoresistance, the key regulators of this process are poorly understood. Here, we use patient-derived single-cell RNA-Seq, multimodal sequencing, tumor microarray staining, and endogenous epigenetic modulation to show that SOX9 is a key driver of chemoresistance in HGSOC. We show that genetic or epigenetic upregulation of SOX9 is sufficient to induce chemoresistance in multiple ovarian cancer cell lines. Moreover, this upregulation induces the formation of a stem-like subpopulation and can significantly decrease tumor chemosensitivity in vivo. Mechanistically, SOX9 expression drives global transcriptional divergence and reprograms the transcriptional program of naïve cells into a stem-like state. Supporting this, our multi-omic single-cell analysis identified a rare cluster of SOX9-expressing cells that are highly enriched for CSCs and chemoresistance-associated stress gene modules in a naïve tumor. Notably, single cell profiles of naïve cells show that chemo treatment results in rapid population-level expression of SOX9 that enriches for a stem-like transcriptional state. Altogether, these findings implicate SOX9 as a critical regulator of early steps of transcriptional reprogramming that leads to chemoresistance through a cancer stem-like state in HGSOC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297350 | GEO | 2025/05/16

REPOSITORIES: GEO

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Project description:Abstract: The cancer stem cell hypothesis has gained currency in recent times but concerns remain about its scientific foundations because of significant gaps that exist between research findings and comprehensive knowledge about cancer stem cells (CSCs). In this light, a mathematical model that considers hematopoietic dynamics in the diseased state of the bone marrow and peripheral blood is proposed and used to address findings about CSCs. The ensuing model, resulting from a modification and refinement of a recent model, develops out of the position that mathematical models of CSC development, that are few at this time, are needed to provide insightful underpinnings for biomedical findings about CSCs as the CSC idea gains traction. Accordingly, the mathematical challenges brought on by the model that mirror general challenges in dealing with nonlinear phenomena are discussed and placed in context. The proposed model describes the logical occurrence of discrete time delays, that by themselves present mathematical challenges, in the evolving cell populations under consideration. Under the challenging circumstances, the steady state properties of the model system of delay differential equations are obtained, analyzed, and the resulting mathematical predictions arising therefrom are interpreted and placed within the framework of findings regarding CSCs. Simulations of the model are carried out by considering various parameter scenarios that reflect different experimental situations involving disease evolution in human hosts. Model analyses and simulations suggest that the emergence of the cancer stem cell population alongside other malignant cells engenders higher dimensions of complexity in the evolution of malignancy in the bone marrow and peripheral blood at the expense of healthy hematopoietic development. The model predicts the evolution of an aberrant environment in which the malignant population particularly in the bone marrow shows tendencies of reaching an uncontrollable equilibrium state. Essentially, the model shows that a structural relationship exists between CSCs and non-stem malignant cells that confers on CSCs the role of temporally enhancing and stimulating the expansion of non-stem malignant cells while also benefitting from increases in their own population and these CSCs may be the main protagonists that drive the ultimate evolution of the uncontrollable equilibrium state of such malignant cells and these may have implications for treatment.

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SOX9 is a driver of a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer [Unenriched_Tumor]

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