Spatial transcriptomics reveals interferon pathway enrichment in early relapsing serous carcinoma

High-grade serous carcinoma (HGSC) is characterized by extensive inter and intra-patient heterogeneity, complicating the identification of reliable prognostic biomarkers and the prediction of treatment response. In clinical practice, the origin of diagnostic biopsies varies, from tubo-ovarian (adnexal) tissue to omental or peritoneal metastatic foci. Whether the different sites provide similar information for molecular characterization or treatment decisions remains unclear. Studies comparing site-specific molecular details and the spatial relationship of HGSC tissue from patients with different treatment outcomes could provide answers to the open questions. Here, we used spatial transcriptomics to profile matched treatment-naive adnexal and omental tumor samples from nine HGSC patients stratified by platinum-free interval (PFI). Pathway enrichment analysis revealed several differences between short and medium- and long PFI tumors, however most of these differences were site-agnostic. Most strikingly, tumor epithelium from short PFI patients showed an inflammatory phenotype driven by increased interferon response signaling, carried by effector interferon-stimulated gene expression at both tumor sites. Further, medium- and long PFI tumors were enriched for proliferative and cell cycle regulatory programs. Differential gene expression and copy-number analyses identified three genes, complement gene C3, and interferon-related genes IFI27 and BST2, consistently associated with short PFI across adnexal and omental sites. These were validated at the tissue level using RNA in-situ hybridization. A case study of copy-number-defined subclones further suggested that this phenotype can arise as a distinct subclonal population within a single tumor. Outcome analysis, using two publicly available ovarian cancer cohorts, showed that high C3 expression was significantly associated with shorter platinum-free survival. Together, these findings implicate complement and interferon signaling as concurrent features of treatment-naive HGSC tumors with early relapse in both adnexal and omental tissue, and nominate C3 as a candidate prognostic biomarker and potential therapeutic target.