Chemoresistant Cancer Cell Lines Are Characterized by Migratory, Amino Acid Metabolism, Protein Catabolism and IFN1 Signalling Perturbations

SIMPLE SUMMARY: While chemoresistance remains a major barrier to improving the outcomes for patients with ovarian cancer, the molecular features, and associated biological functions, which underpin chemoresistance in ovarian cancer remain poorly understood. In this study we aimed to provide insight into the proteins and metabolites, and their associated biological pathways, which play a role in conferring chemoresistance to ovarian cancer. Through mass spectrometry analysis comparing the proteome and metabolome of chemosensitive vs chemoresistant ovarian cancer cell lines we revealed numerous perturbations in signalling and metabolic pathways in chemoresistant cells. Further comparison to primary cells taken from patients with chemoresistant or chemosensitive disease identified a shared dysregulation in cytokine and type 1 interferon signalling. Our research sets the foundation for a deeper understanding of the proteomic and metabolomic features of chemoresistance and identifies type 1 interferon signalling as a common feature of chemoresistance. ABSTRACT: Chemoresistance remains the major barrier to effective ovarian cancer treatment. The molecular features and associated biological functions of this phenotype remain poorly understood. We developed carboplatin-resistant cell line models using OVCAR5 and CaOV3 cell lines with the aim of identifying chemoresistance-specific molecular features. Chemotaxis and CAM invasion assays revealed enhanced migratory and invasive potential in OVCAR5-resistant, compared to parental cell lines. Mass spectrometry analysis was used to analyse the metabolome and proteome of these cell lines, and was able to separate these populations based on their molecular features. It revealed signalling and metabolic perturbations in the chemoresistant cell lines. A comparison with the proteome of patient-derived primary ovarian cancer cells grown in culture showed a shared dysregulation of cytokine and type 1 interferon signalling, potentially revealing a common molecular feature of chemoresistance. A comprehensive analysis of a larger patient cohort, including advanced in vitro and in vivo models, promises to assist with better understanding the molecular mechanisms of chemoresistance and the associated enhancement of migration and invasion.