SOX9 is a driver of a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer [Unenriched_Tumor]
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. Overall design: Multimodal single-cell RNA and ATAC seq of a whole tissue human high grade serous ovarian tumor before patient received neo-adjuvant chemotherapy