Local androgen and 11-oxyandrogen metabolism and signaling emerges as a novel prognostic and therapeutic axis in high-grade serous ovarian cancer

Abstract Background High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy, exhibiting marked heterogeneity that complicates treatment. The implications of intratumoral androgen metabolism and signalling, particularly involving 11-oxygenated androgens, in HGSOC remains poorly understood. Methods We analysed expression of key androgen-metabolizing enzymes and androgen receptor (AR) in relation to tumor site, chemotherapy response, and survival using two independent public HGSOC cohorts. Quantitative gene expression and steroid metabolism assays upon incubation with classic and 11-oxyandrogen precursors were performed in six HGSOC cell lines and one normal ovarian epithelial cell line. Untargeted transcriptomic and metabolomic profiling were performed to assess cellular responses to potent classic and 11-oxygenated androgens in the AR -positive OVSAHO cell line. Results Differential expression of steroid-metabolizing enzymes and AR were observed between primary and metastatic tumors and chemo-sensitive and chemo-resistant tumors. Higher intra-tumoral expression of HSD11B2 , HSD17B2 , and AR correlated with improved survival, whereas elevated PAPSS1/2 and HSD17B4 predicted poorer outcomes. In vitro, classic androgen precursors showed limited conversion to bioactive androgens and did not generate 11-oxyandrogens. In contrast, 11-oxyandrogen precursors were efficiently converted to the potent AR agonist 11-keto-testosterone (11KT) in chemo-sensitive HGSOC cell lines, but not in chemo-refractory or control lines. Potent classic and 11-oxyandrogens triggered stress-adaptive and proliferative transcriptional programs, with 11-keto-dihydrotestosterone (11KDHT) additionally driving widespread metabolic reprogramming, including depletion of amino acids, glutathione, and nucleotide sugar metabolites. These changes were associated with a trend toward reduced cell proliferation. Conclusions Our findings offer mechanistic insight into local androgen and 11-oxyandrogen metabolism and signalling in HGSOC and reveal steroid-induced cellular vulnerabilities that may synergize with chemotherapy or molecularly targeted therapies. These results further support the therapeutic potential of modulating steroid pathways in HGSOC.