Glycomics Profiling Reveals a Stromal Chondroitin-4-sulfate State that Shapes Platinum Response in Ovarian Cancer

Abstract

For women with advanced ovarian cancer (OC), remission is typically achieved through surgery and platinum-based combination chemotherapy, but the duration of response varies widely, and reliable biomarkers of platinum sensitivity remain limited. Because tumor-associated glycosaminoglycans (GAGs) influence extracellular signaling and drug interactions, but are not directly resolved by conventional transcriptomic approaches, we investigated whether direct glycomics profiling could identify a functionally relevant determinant of platinum response. Glycan reductive isotope labeling-LC/MS of ovarian cancer patient-derived xenografts (PDXs) showed that carboplatin-resistant tumors were enriched for chondroitin-4-sulfate (C4S). Single-cell transcriptomic analyses localized candidate proteoglycan scaffolds, including VCAN and BGN, primarily to stromal fibroblast compartments, supporting a stromal matrix source while underscoring that RNA measurements cannot define mature GAG abundance or fine structure. Analysis of tissue microarrays representing multiple ovarian cancer histotypes revealed high C4S expression, including in subtypes with intrinsic platinum resistance. CRISPR-mediated double XYLT1 and XYLT2 knockout reduced C4S levels, slowed ES2 tumor growth, reduced spheroid invasion, altered intraperitoneal dissemination, and eliminated ascites in the ES2 model. XYLT1/2 knockout also shifted platinum pharmacology: carboplatin uptake and DNA platination increased, whereas Triplatin accumulation and activity decreased. In PDX models, tissue rVAR2-V5 staining correlated with direct glycomics measurements and identified carboplatin-resistant tumors selectively sensitive to the GAG-targeting platinum agent Triplatin. These findings nominate a stromal-associated C4S-rich extracellular state as a non-genetic determinant of platinum response and tumor behavior, and support tissue-level C4S assessment for biomarker-guided evaluation of Triplatin.