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A key histopathological feature of pancreatic ductal adenocarcinoma (PDA) that is also associated with its innate clinical and biological aggressiveness is its pronounced desmoplastic (stromal) reaction. Desmoplasia generates a nutrient and oxygen-deprived environment in PDA that is unique to the disease. The resultant redox and metabolic adaptations thus create cancer-specific vulnerabilities that could potentially be exploited. Our central hypothesis is that PDA cells harness reactive oxygen species (ROS) as selective secondary messengers to support cancer cell viability and tumor-stroma co-evolution.
The goal of our research is to leverage the ability of PDA cells to regulate levels of reactive oxygen species towards the development of more effective therapies for this highly lethal malignancy. The cytoprotective transcription factor NRF2 is a central regulator of redox homeostasis and is up-regulated in PDA. As transcription factors are difficult to target therapeutically, our laboratory seeks to comprehensively characterize the mechanisms used by NRF2 to promote PDA such that more feasible approaches to counter its effects in PDA may be developed. In pursuit of this goal, genetically engineered mouse models (GEMM), ex-vivo organoid co-culture systems, and patient-derived organoid transplantation models will be used to establish a discovery pipeline and in vivo validation platforms that will facilitate the design of integrated intervention strategies for a disease involving complex interactions between the tumor and the stroma.