Integrative multi-omic analysis identifies neuronal reprogramming and vascular remodeling as hallmarks of recurrent high-grade serous ovarian carcinoma

Background: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian cancer, with over 80% of patients experiencing recurrence after initial therapy. Recurrent disease is typically chemoresistant and remains the leading cause of gynecologic cancer mortality, yet the molecular changes driving recurrence, particularly at the cell type-specific level, are poorly understood. Objective: To define cell type resolved transcriptional programs that distinguish late primary from recurrent disease, to place these programs into a stage aligned cellular context from benign tissue through recurrence, and to nominate robust biomarkers with external replication and genomic concordance. Methods: Matched late primary and recurrent HGSOC specimens were profiled by snRNAseq with additional benign and early tumors included for stage contextualization. Paired pseudobulk differential expression between late primary and recurrence was performed using DESeq2 and limma voom with patient blocking, low expression filtering, trimmed mean normalization, and false discovery rate control. Replication of 46 significant genes was assessed in four external cohorts. In addition, somatic variant and copy number profiles from late primary tumors generated by whole exome sequencing were compared with transcriptional effects at panel loci. A transcriptional signature was related to time to recurrence using exact rank statistics with bootstrap assessment of robustness. Results: snRNAseq of matched late primary and recurrent HGSOC revealed a recurrence program that maps to tumor associated endothelium and to a neuronal lineage state in malignant epithelium. FLT1 STC1 and CA2 and selective suppression of the endothelial long noncoding RNA MEF2C AS1; FLT1 and CA2 together with MEF2C AS1 constitute novel recurrence associated endothelial markers in this disease. Malignant cells exhibited a novel neuronal reprogramming signature defined by induction of NTM and KCNQ5 with reciprocal downregulation of PEG3 , and stromal compartments showed reduced ABCA8 and the novel marker PLCXD3 . Whole exome copy number profiling of late primary tumors provided directional concordance with the transcriptome, including deep loss at KCNQ5 , late stage copy number reduction at FLT1 , ESM1, and NTM aligned with their induction at recurrence, and late stage gain at C7 and PLCXD3 aligned with its suppression at recurrence. Conclusion: Our integrative multi‑omic analysis reveals that recurrent HGSOC is characterized by coordinated vascular remodeling in tumor‑associated endothelium and neuronal reprogramming in malignant epithelium, accompanied by stromal reconfiguration. These findings nominate cell‑state-specific biomarkers and pathways for prospective validation and therapeutic targeting in recurrent disease.