Reconstruction of epithelial transcriptional trajectories reveals heterogeneous progression and early therapy-resistance programs in high-grade serous carcinoma precursors

Vollständiger Abstract

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Abstract Background Serous-tubal intraepithelial-carcinoma (STIC) is considered the principal precursor of tubo-ovarian high-grade serous-carcinoma (HGSC), yet its biological uniformity, progression risk and potential response to poly(ADP-ribose) polymerase-inhibitors (PARPi) remain poorly defined. Methods We performed trajectory-based transcriptomic reconstruction of Fallopian-tube epithelial regions spanning histologically normal-appearing epithelium, precursor lesions, STIC, and invasive carcinoma using pseudotime inference and publicly available spatial transcriptomic data. Gene expression and pathway dynamics were defined along pseudotime, and interpatient heterogeneity examined at both lesion and patient levels. Transcriptional signatures associated with PARPi-resistance were quantified across STICs, BRCA -mutant and BRCA -wild type subtypes. Results Trajectory inference captured a continuous transcriptional progression from histologically normal-appearing epithelium to HGSC, with STICs occupying heterogeneous evolutionary positions rather than a single precursor state. Incidental isolated STICs (STICi) spanned early to later pseudotime states and frequently aligned with loss-of-cilium organisation and less advanced epithelial phenotypes. STICs associated with concurrent cancer (STICc) exhibited more advanced malignant progression signatures, including cell-cycle activation, epithelial-to-mesenchymal transition (EMT), interferon signaling, and DNA-repair. Histologically similar lesions occupied divergent pseudotime positions with marked interpatient heterogeneity. PARPi resistance–associated signatures were variably enriched across precursor and precancer-stage lesions, with persistence into invasive disease. Conclusions STICs are heterogeneous and occupy distinct evolutionary positions along a continuum, suggesting potentially different degrees of transcriptional advancement from histologically normal-appearing epithelium toward HGSC. STICi differ from STICc which harbour signatures of more advanced malignant progression. The heterogeneous enrichment of PARPi resistance–associated transcriptional programs across STICs suggests that precursor lesions may differ in their predicted responsiveness; if confirmed functionally, this would argue against assuming uniform efficacy of PARPi-based primary prevention and would support investigation of stratified approaches. Future research should explore evolutionary-trajectory informed biomarkers for risk stratification and early interception strategies.