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Receptor for hyaluronan-mediated motility isoform B (RHAMM B) in Pancreatic Cancer Metastasis

胰腺癌转移中透明质酸介导的运动异构体 B (RHAMM B) 的受体

基本信息

批准号：
10669788
负责人：
Yi-Chieh Nancy Du
金额：
$ 38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669788
关键词：
3-Dimensional Automobile Driving Biogenesis Biological Assay Biology Biosensor Cell Line Cells Complex Data Diagnosis Diagnostic Procedure Disease Disseminated Malignant Neoplasm Dominant-Negative Mutation Enzymes Event Fluorescence Resonance Energy Transfer Genes Genetically Engineered Mouse Guanine Nucleotide Exchange Factors HMMR gene Histologic Human In Vitro Incidence Invaded Islet Cell Tumor KRAS oncogenesis Length Lipids Lipolysis Liver Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Mediating Metabolic Metastatic Neoplasm to the Liver Molecular Neoplasm Metastasis Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Prognostic Factor Protein Isoforms Publishing RHAMM protein RNA Splicing Reporting Role Signal Pathway Signal Transduction Site Survival Rate System Testing Therapeutic Translating Tumor Cell Line Work Xenograft Model Xenograft procedure cancer cell cancer type cell motility effective therapy improved in vivo insight knock-down migration mouse model mutant new therapeutic target novel novel strategies novel therapeutic intervention overexpression pancreas xenograft pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell patient derived xenograft model pharmacologic phosphoproteomics prognostic programs protein expression receptor function rho success technique development therapeutic development treatment strategy tumor tumor xenograft

项目摘要

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.

项目总结