Does neoadjuvant chemotherapy bias the transcriptomic profile of platinum-sensitive advanced high grade serous ovarian cancer patients towards a resistant phenotype? Findings from a gene expression meta-analysis

BackgroundChemoresistance is the key determinant of long-term survival in advanced high-grade serous ovarian cancer (HGSOC). The molecular mechanisms underlying chemoresistance in clinical populations are not clearly known. The study aimed to analyze the molecular mechanisms promoting chemoresistance, as well as neoadjuvant chemotherapy (NACT) induced sensitive-to-resistant transformation in advanced-HGSOC patients. MethodsRNA-sequencing data from Gene Expression Omnibus (GEO) database was systematically searched and extracted. Pre-chemotherapy (resistant vs sensitive) and chemosensitive (post-chemotherapy vs pre-chemotherapy) subgroup analyses were performed. For each subgroup, differential-gene-expression (DGE) meta-analysis and downstream analysis for pathway enrichment, protein-protein network and cancer stem cell expression were performed. ResultsThree bulk RNA-sequencing datasets (GSE162714, GSE173420, GSE227100) were included in the analysis. Prechemotherapy inherent-resistant samples showed upregulation of inflammation, epithelial-mesenchymal-transition processes, higher stromal proportion in tumors with upregulation of cancer-associated-fibroblasts (CAFs), and some of the cancer stem cell (CSC) markers over the sensitive phenotype. On the other hand, exposure to NACT in chemosensitive patients led to upregulation of inflammation, immune evasion, CSC-led proliferation and drug-efflux-pump overexpression, with increased immune and CAF cells in stroma mirroring an inherent-resistance phenotype, implying a sensitive to resistant transformation. ConclusionInflammatory microenvironment, EMT and CSCs play a key role in promoting chemoresistance and post-NACT sensitive-resistant transformation.