SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer
Alexander J. Duval, … , Daniela Matei, Mazhar Adli
Alexander J. Duval, … , Daniela Matei, Mazhar Adli
Published October 1, 2025
Citation Information: J Clin Invest. 2025;135(19):e186467. https://doi.org/10.1172/JCI186467.
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Research Article Oncology

SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer

Abstract

Chemotherapy resistance remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The drug-tolerant cells may originate from a small population of inherently resistant cancer stem cells (CSCs) in primary tumors. In contrast, sufficient evidence suggests that drug tolerance can also be transiently acquired by nonstem cancer cells. Regardless of the route, key regulators of this plastic process are poorly understood. Here, we utilized multiomics, tumor microarrays, and epigenetic modulation to demonstrate that SOX9 is a key chemo-induced driver of chemoresistance in HGSOC. Epigenetic upregulation of SOX9 was sufficient to induce chemoresistance in multiple HGSOC lines. Moreover, this upregulation induced the formation of a stem-like subpopulation and significant chemoresistance in vivo. Mechanistically, SOX9 increased transcriptional divergence, reprogramming the transcriptional state of naive cells into a stem-like state. Supporting this, we identified a rare cluster of SOX9-expressing cells in primary tumors that were highly enriched for CSCs and chemoresistance-associated stress gene modules. Notably, single-cell analysis showed that chemo treatment results in rapid population-level induction 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 lead to chemoresistance through a CSC-like state in HGSOC.

Authors

Alexander J. Duval, Fidan Seker-Polat, Magdalena Rogozinska, Meric Kinali, Ann E. Walts, Ozlem Neyisci, Yaqi Zhang, Zhonglin Li, Edward J. Tanner III, Allison E. Grubbs, Sandra Orsulic, Daniela Matei, Mazhar Adli

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Figure 2

SOX9 is induced in HGSOC patients following platinum treatment and is highly associated with transcriptional malleability.

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SOX9 is induced in HGSOC patients following platinum treatment and is hi...
(A) Schematic overview depicting when samples were collected from patients. (B) Uniform Manifold Approximation and Projection (UMAP) feature plot showing EPCAM expression in a longitudinal scRNA-Seq dataset representing HGSOC tumors from 11 patients consisting of 51,786 total cells. (C) UMAP plot showing epithelial cells only from the longitudinal dataset color coded for treatment-naive and post-NACT cells. (D) UMAP feature plot showing SOX9 expression in epithelial cells in the longitudinal dataset. (E) Violin plot showing SOX9 expression in epithelial cells in treatment-naive versus post-NACT cells. P value was calculated using Wilcoxon’s signed-rank test. (F) Pseudo-bulk, patient-paired box plot of SOX9 expression in epithelial cells in treatment-naive versus post-NACT cells. P value was calculated using a paired Wilcoxon’s signed-rank test. (G) Violin plot showing transcriptional divergence per epithelial cell separated between treatment-naive versus post-NACT cells. P value was calculated using Wilcoxon’s signed-rank test. (H) Scatterplot showing –log10(FDR) for the Spearman’s rank correlation between epithelial transcriptional divergence and TF expression as well as differential expression between treatment-naive versus post-NACT cells. Box-and-whisker plots depict median, interquartile range, and data range.