WNT enhancing signals in pancreatic cancer are transmitted by LGR6

The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.