Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer.

摘要: Notch controls pancreatic differentiation during development and is reactivated in cancer. In recent years, the importance of signaling tumorigenesis has become increasingly evident; however, it remains unclear how activities are regulated this context. Here we report differential regulation receptors by Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats extracellular domain, pathogenesis Kras-induced ductal adenocarcinoma (PDAC). We show that Lfng uniquely expressed a subset acinar cells adult pancreas. Deletion Kras(LSL-G12D/+);Pdx1-Cre mouse model caused increased activation Notch3 throughout PDAC initiation progression, Notch1 after onset disease, associated with marked upregulation target gene Hes1. also resulted accumulation Aldh1-positive cell population. found loss significantly accelerated Kras-initiated shortened survival mice. Interestingly, Lfng-deficient tumors showed propensity for poorly differentiated state features epithelial-to-mesenchymal transition. Likewise, knockdown LFNG human lines elevated activation, either proliferation or expanded downregulation Tgfb1, Tgfb2 Tgfbr2 expression wild-type pancreas at all ages examined, onset, as well reduced phospho-Smad2 levels tumors. provide evidence regulates transforming (TGF)-β through Notch-mediated transcriptional repression TGF-β pathway genes. Taken together, our results reveal potent tumor-suppressive function crosstalk between pathways pancreas, provides new insight into signals involved disease progression.