Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMM B promoted liver metastasis. It was unknown whether RHAMM B is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMM A and RHAMM B , by RNA-Seq analysis of primary PNETs and liver metastases. RHAMM B , but not RHAMM A , was significantly upregulated in liver metastases. RHAMM B was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMM A , carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMM B was substantially higher than RHAMM A in pancreatic ductal adenocarcinoma (PDAC). RHAMM B , but not RHAMM A , correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMM B -driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMM B , but not RHAMM A , in promoting PNET metastasis in part through EGFR signaling. RHAMM B can thus serve as a prognostic factor for pancreatic cancer.