Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample

Abstract

AbstractBackgroundChemoresistance and tumor recurrence remain a significant challenge in ovarian cancer. Particularly in the context of platinum resistance, many mechanisms have been identified, including the activation of cellular processes like epithelial-mesenchymal transition (EMT), which generates cells with stemness characteristics. Current models of platinum resistance are limited or not adequate representations of the heterogeneity of the disease. Thus, to advance our understanding of chemoresistance in the context of cancer stem cells (CSC) in ovarian cancer, this study aims to develop an effective model for cisplatin resistance using a patient-derived cancer stem-like sample.MethodsPDX4, a patient-derived cancer cell line with stem-like properties, was exposed to increasing concentrations of cisplatinin vitroin parallel with vehicle treated cells. Once chemoresistance was established and confirmed, the resistance model was validated through comprehensive molecular profiling through RNA- and miRNA-sequencing, followed by the assessment of alterations in cell morphology, protein expression, and functional properties in the context of EMT and cancer stemness. Moreover, we explored potential signaling pathways involved in cisplatin resistance in these stem-like cancer cells.ResultsOur findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin resistant PDX4 compared to their sensitive counterparts. Furthermore, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic. JAK-STAT, hypoxia, and PI3K signaling pathways were enriched in these cells, indicating the activation of pathways that assist in DNA damage tolerance and cellular stress management.ConclusionThis novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapeutic strategies tailored to combat resistance in stem-like ovarian cancer.