Stage-Specific Rewiring of PI3K–AKT Signaling During Serous Ovarian Cancer Progression: An Integrated Transcriptomic and Network Analysis

Abstract

High-grade serous ovarian cancer (HGSOC) exhibits substantial molecular heterogeneity during disease progression. We investigated stage-specific changes in PI3K–AKT-associated signaling programs from early tumorigenesis to metastatic disease. Two publicly available microarray datasets, GSE36668 (normal, borderline, and carcinoma; n = 4 per group) and GSE73064 (primary tumor, ascites, and metastasis; n = 5 per group), were analyzed using differential expression, gene set enrichment, protein–protein interaction network analysis, and hub-gene identification. PI3K–AKT-associated genes were subsequently characterized by functional enrichment, exploratory survival analysis using KM Plotter, and independent stage-stratified validation in TCGA-OV. Survival analyses were considered exploratory because KM Plotter-derived p-values were not adjusted for multiple testing. Carcinoma-associated genes were predominantly linked to extracellular matrix remodeling and receptor tyrosine kinase-mediated PI3K signaling. Ascites-associated genes were enriched in integrin-dependent signaling and microenvironmental adaptation, whereas metastasis-associated genes formed inflammatory and survival-related modules involving IL6, JAK1, PTK2, AREG, EIF4E, and HSP90B1. In stage-stratified TCGA-OV analysis, all seven metastasis-associated genes were significantly associated with overall survival in Stage IV disease, supporting the prognostic relevance of the metastatic module. HGSOC progression is characterized by stage-associated reorganization of PI3K–AKT-related signaling rather than uniform pathway activation. The identified molecular programs suggest a transition from RTK-associated proliferative signaling in carcinoma to integrin-dependent survival adaptation in ascites and inflammatory survival signaling during metastasis.