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.