Summary
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of cancer-associated fibroblasts (CAFs) and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. Here, we uncovered the upregulation of NetrinG1 (NetG1) in CAFs and its binding partner NetrinG1 ligand (NGL-1) in PDAC cells and patient tissue samples. Using a three-dimensional culturing system, we observed that the NetG1/NGL-1 axis controls key pro-tumorigenic features of CAFs and PDAC cells, in cell autonomous and reciprocal manners. Results were confirmed in vivo using patient tissues and in a murine PDAC model in which NGL-1 ablation in PDAC cells significantly halted tumor growth. Thus, this study identifies two potential targets for PDAC, both tumoral and microenvironmental.
Significance PDAC has a 5-year survival rate of ~8% and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets and discern their functional roles. Using patient tissue and data, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified NetG1 and NGL-1 as major promoters of PDAC tumorigenesis. NetG1+ CAFs supported PDAC survival, through NetG1/NGL-1 mediated nutritional supply, dependent on glutamate metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of PDAC cells. NGL-1 controlled tumor cell fitness in vitro and in vivo, likely through metabolic communication with CAFs. Overall, we identified two putative targets in different cellular compartments in PDAC and disrupting solely one arm of the NetG1/NGL-1 axis significantly stunted tumorigenesis.
