PROJECT SUMMARY The 5-year survival is the lowest for cancers of the pancreas (<10%) among all cancers and the incidence of pancreatic cancer continues to increase. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), followed by pancreatic neuroendocrine tumor (PNET). Pancreatic cancer is usually deadly due to metastatic dissemination and insufficient therapeutics. Factors driving metastasis of pancreatic cancer remains largely unclear. There is an urgent need to understand the biology of pancreatic cancer metastasis and develop new therapeutic strategies. We were the first to report that Receptor for hyaluronan-mediated motility isoform B (RHAMMB), but not the full length RHAMMA, promotes metastasis of PNET. We found that among different splice isoforms, RHAMMB was significantly upregulated in human PDAC, and that higher RHAMMB predicted poorer survival of PDAC. However, whether RHAMMB promotes PDAC metastasis is still unknown and will be determined in this proposal work. Our preliminary data showed that RHAMMB overexpression induced RhoA signaling, migration, 3D spheroid invasion, and lipid droplet (LD) biogenesis in both PDAC and PNET cell lines, while RHAMMB knockdown or pharmacological inhibition of RhoA signaling caused opposite effects. We hypothesis that RHAMMB promotes pancreatic cancer metastasis through RhoA signaling/LD biogenesis and this RHAMMB /RhoA/LD axis represents a novel therapeutic target. To test this hypothesis, we will use multiple experimental systems, including cell lines, orthotopic tumor xenograft, genetically engineered mouse models, and patient-derived xenografts. The findings will be cross- examined. The success of this proposed study will establish the mechanisms by which RHAMMB promotes pancreatic cancer metastasis and translated into new therapeutic approaches for treatment of this devastating cancer.