Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth
Menée à l'aide de lignées cellulaires et de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel les fibroblastes associés au cancer, via l'autophagie dépendante de la protéine NUFIP1, sécrète des nucléosides et soutient la croissance tumorale
Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.
Nature Cancer 2022