Abstract 4751: SOX4 upregulation contributes to ovarian cancer initiation through a stress-adaptation program

Abstract High-grade serous carcinoma (HGSC) is a clinically aggressive subtype of ovarian epithelial cancer, mainly because of late diagnosis and the development of therapy resistance. Our Ovarian Precancer Atlas study provides a molecular map of HGSC development, and one of our most exciting findings is the identification of a transcription factor, SOX4. SOX4 is a developmentally regulated transcription factor belonging to the SRY-related HMG-box family. It regulates cell fate, lineage determination, and differentiation. Our spatial transcriptomic and immunohistochemical analyses show an upregulation of SOX4 in HGSC and its precancerous lesion, STIC. However, the biological significance of this finding remains unclear. Spatial transcriptomics and Immunohistochemical analyses confirmed progressive SOX4 upregulation in STIC and HGSC tissues. siRNA-mediated SOX4 knockdown in fallopian tube epithelial (FT241, FT2821) and HGSC (UWB1.289 ± BRCA1) models reduced proliferation and colony formation, indicating that endogenous SOX4 is required for cell growth and survival. Conversely, acute SOX4 induction in doxycycline-inducible OVCAR8 models decreased proliferation, clonogenicity, and wound healing, while elevating ROS and ProteoStat-measured proteotoxic stress—indicating a SOX4-induced cellular stress environment. RNAseq analyses also revealed expression of genes involved in reprogramming and redox homeostasis. When the inducible cells were cultured continuously under doxycycline for approximately two months, they underwent stable phenotypic remodeling and regained proliferative fitness, paralleling the enhanced tumorigenicity observed in vivo. This suggests that chronic SOX4 activation drives a transition from an initial stress-induced to a stress-adapted proliferative state that enables malignant progression. Before this adaptive remodeling is complete, SOX4-high cells exhibited heightened vulnerability to ER stress and proteasome inhibition—revealing a stress-sensitized therapeutic window selectively targetable in SOX4-high tumors. SOX4-induced cells showed synergistic reduction in cell proliferation and apoptosis when combined with MG132 or Tunicamycin. This study reveals a new mechanism by which transformed cells exploit SOX4-induced proteomic stress and turn it to their advantage in tumor progression after overcoming a selection pressure. SOX4 induces an oxidative/proteotoxic stress state that temporarily hinders growth in vitro but promotes tumorigenicity in vivo through adaptive remodeling. This process highlights a time-limited, stress-sensitive therapeutic window—before full adaptation, during which ER and proteasome challenges are especially effective. These findings position SOX4 as both a mechanistic driver of stress adaptation in HGSC carcinogenesis and a biomarker to select HGSC patients for targeted stress-modulating therapies. Citation Format: Jayaprakash Mandal, Brielle Hayward Piatkovskyi, Md Masud Rana, Tu-Yung Chang, Tian-Li Wang, Ie-Ming Shih, . SOX4 upregulation contributes to ovarian cancer initiation through a stress-adaptation program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4751.