BICC1 drives pancreatic cancer stemness and chemoresistance by facilitating tryptophan metabolism
Menée à l'aide de lignées cellulaires d'adénocarcinome canalaire du pancréas, d'organoïdes et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la protéine BICC1 favorise l'acquisition, par les cellules cancéreuses, de propriétés similaires à celles des cellules souches et d'une résistance à la chimiothérapie en facilitant le métabolisme du tryptophane
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD+ synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance. BICC1 promotes tryptophan metabolism in PDAC, resulting in stemness and resistance to chemotherapy.