Targeting Cancer-Associated Fibroblast As A Novel Strategy To Treat Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by a heavy desmoplastic, nutrient deprived and immunosuppressive microenvironment, which projects it to become the second leading cause of cancer-related death by 2030. Cancer-associated fibroblasts (CAFs) represent the main producer of extracellular matrix (ECM), and have a dual role in contributing both to immune suppression and direct support of cancer cells with supplies. CAFs are found to be divided into several populations among which the main are inflammatory CAFs and myofibroblasts. In this thesis I’ll discuss deeper the differentiation of those two fibroblast subpopulations and how IL1 and TGFβ lead their differentiation. Inflammatory CAFs have been associated with a more tumor-supportive phenotype while myofibroblasts exert anti-tumor functions and their targeting can lead to a more aggressive PDA phenotype. In particular, I’ll discuss a study in which the depletion of collagen improves tumor growth. Moreover, CAFs directly support cancer cell survival and proliferation by nutrient transfer in a Netrin G1-dependent manner, a neuronal cell-cell adhesion mediator, involved in axon guidance. All these studies confirm the general idea that it is necessary to better characterize stromal targets to improve the efficacy of cancer treatments.