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

• 批准号: 10522370
• 负责人: Yi-Chieh Nancy Du
• 金额: $ 38.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10522370
• 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; 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; Metastatic to; Molecular; Neoplasm Metastasis; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacology; 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; base; cancer cell; cancer type; 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; phosphoproteomics; prognostic; protein expression; receptor function; rho; success; technique development; therapeutic development; treatment strategy; tumor; tumor xenograft

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.

项目摘要 5年生存率是所有癌症中胰腺癌（<10％）的最低生存期，并且发生率是 胰腺癌继续增加。胰腺癌最常见的类型是胰腺导管 腺癌（PDAC），其次是胰腺神经内分泌肿瘤（PNET）。胰腺癌通常是 致命的是由于转移性传播和治疗剂不足而导致的。驱动胰腺转移的因素 癌症在很大程度上不清楚。迫切需要了解胰腺癌的生物学 转移并制定新的治疗策略。 我们是第一个报告透明质酸介导的运动受体同工型B（Rhammb）的人，但不是完整的 长度Rhamma，促进PNET的转移。我们发现在不同的剪接同工型中，rhammb是 在人PDAC中显着上调，较高的RHAMMB预测PDAC的存活较差。 但是，rhammb是否促进PDAC转移仍然未知，并将在此确定 提案工作。我们的初步数据表明，Rhammb的过表达诱导RhoA信号传导，迁移， PDAC和PNET细胞系中的3D球体入侵和脂质液滴（LD）生物发生，而Rhammb RhoA信号传导的敲低或药理抑制会导致相反的影响。我们假设 RHAMMB通过Rhoa信号传导/LD生物发生促进胰腺癌转移和这种rhammb /rhoa/ld轴代表一个新型的治疗靶标。 为了检验该假设，我们将使用多个实验系统，包括细胞系，原位肿瘤 异种移植物，基因工程的小鼠模型和患者衍生的异种移植物。调查结果将是交叉的 检查。这项拟议的研究的成功将确定rhammb促进的机制 胰腺癌转移，并转化为新的治疗方法来治疗这种毁灭性的 癌症。