Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12943-019-1018-y) contains supplementary material, which is available to authorized users.

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

“… 122 – 125 Upon HA binding, both CD44 and RHAMM function as a co‐receptors to activate other transmembrane tyrosine kinases, including epidermal growth factor receptor, c‐MET, and platelet‐derived growth factor receptor to promote tumor progression and therapeutic resistance. 117 , 126 , 127 In addition, CD44 and RHAMM ligation also activates kinases including ERK, FAK, Src to promote cell migration, invasion, and survival. 118 , 128 – 130 Importantly, downstream signaling and functional output of CD44 ligation is greatly dependent on the molecular weight of bound HA.…”

Insights into the biology and treatment strategies of pancreatic neuroendocrine tumors

“…RHAMM is not expressed in normal adult pancreas and its expression is restricted in other normal adult human tissues (98). Our studies showed that RHAMM B is overexpressed in human primary PNETs and liver metastases and it is a key driver for liver metastasis of PNET in mouse models (99). Therefore, RHAMM B could be a potential therapeutic target in PNETs.…”

High Expression of Hyaluronan-Mediated Motility Receptor Predicts Adverse Outcomes: A Potential Therapeutic Target for Head and Neck Squamous Cell Carcinoma

“…The main reason is that the number of patients tested by immunohistochemistry is too small, just only 35 patients (26). Although this is the first study to show that HMMR expression could be a prognostic factor for HNSCC, a large number of relevant studies have revealed that HMMR expression could be an adverse prognostic biomarker for various tumors (14)(15)(16)(17)(18). Considering that HMMR is a strong prognostic factor, we constructed a nomogram combining the HMMR expression and clinical data.…”