Modulation of redox metabolism negates cancer-associated fibroblasts-induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer

Abstract

The complex interplay between cancer cells and their microenvironment remains a major challenge in the design and optimization of treatment strategies for pancreatic ductal adenocarcinoma (PDAC). Recent investigations have demonstrated that mechanistically distinct combination therapies hold promise for treatment of PDAC, but effective clinical translation requires more accurate models that account for the abundant tumor-stroma and its influence on cancer growth, metabolism and treatment insensitivity. In this study, a modular 3D culture model that comprised PDAC cells and patient-derived cancer-associated fibroblasts (CAFs) was developed to assess the effects of PDAC-CAF interactions on treatment efficacies. Using newly-developed high-throughput imaging and image analysis tools, it was found that CAFs imparted a notable and statistically significant resistance to oxaliplatin chemotherapy and benzoporphyrin derivative-mediated photodynamic therapy, which associated with increased levels of basal oxidative metabolism. Increased treatment resistance and redox states were similarly observed in an orthotopic xenograft model of PDAC in which cancer cells and CAFs were co-implanted in mice. Combination therapies of oxaliplatin and PDT with the mitochondrial complex I inhibitor metformin overcame CAF-induced treatment resistance. The findings underscore that heterotypic microtumor culture models recapitulate metabolic alterations stemming from tumor-stroma interactions. The presented infrastructure can be adapted with disease-specific cell types and is compatible with patient-derived tissues to enable personalized screening and optimization of new metabolism-targeted treatment regimens for pancreatic cancer.