The Janus kinase 1 is critical for the postnatal development of the pancreas and cancer progression
Inflammatory cytokines promote the development of pancreatic ductal adenocarcinoma (PDAC), but the functions of specific intracellular signaling mediators in this process are less well-defined. In this study, we discovered that the Janus kinase 1 (JAK1) is critical for the early postnatal growth of the exocrine pancreas. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate that JAK1 deficiency prevents the formation of KRASG12D-induced pancreatic tumors, and we established that JAK1 is essential for the constitutive activation of STAT3 whose activation is a prominent characteristic of PDAC. We identified C/EBPd as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPd was sufficient to rescue the growth of JAK1-deficient tumorspheres. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPd and may serve as a molecular target for PDAC prevention and treatment. Overall design: Comparative gene expression profiling analysis of RNA-seq data forsix isogenic pairs of mouse pancreatic cancer cell lines before and after Cre-mediated deletion of JAK1.