Abstract Pancreatic cancer is a leading cause of cancer-related death. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), and pancreatic neuroendocrine tumor (PNET) is the second common malignancy of pancreas. Pancreatic cancer patients are often diagnosed with metastatic diseases. The 5-year survival is lowest for pancreatic cancer among all cancers. There is an urgent need to understand the key regulators for pancreatic cancer metastasis and develop new therapeutic strategies. We found that Receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in pancreatic cancer, but it is absent or limited in normal human tissues and not expressed in adult pancreas. RHAMM was initially identified as a protein that binds to hyaluronic acid (HA). RHAMM promotes HA-induced motility, modulates cytoskeletal organization, and activates extracellular-regulated kinase (Erk). RHAMM encodes 18 exons and alternative splicing yields different isoforms, RHAMMv1-4. We found that RHAMMB (known as RHAMMv3) is the most prominent alternative splicing isoform in PDAC and PNET, and high RHAMMB mRNA levels correlate with inferior survival of pancreatic cancer patients in TCGA cohort. We demonstrated that RHAMMB overexpression promotes metastasis of pancreatic cancer in mouse models and knockdown of RHAMM by shRNA suppresses migration and metastasis. Given RHAMM’s tumor-specific overexpression patten, we developed nanoparticles to target RHAMMB-overexpressing pancreatic cancer. We demonstrated that RHAMM-targeting nanoparticles loaded with multiple therapeutics can be used as a systemic therapy to suppress RHAMMB-overexpressing tumors in immunocompetent mice. Taken together, RHAMMB plays an important role for pancreatic cancer metastasis and serves as a therapeutic gateway for pancreatic cancer treatment. Citation Format: Xiang Chen, Tiantian Zhang, Seung Koo Lee, Dunrui Wang, Zhengming Chen, Ching-Hsuan Tung, Yao-Tseng Chen, Yi-Chieh Nancy Du. RHAMMB promotes pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B023.