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.

项目概要 胰腺癌的 5 年生存率是所有癌症中最低的（<10%），并且胰腺癌的发生率 胰腺癌持续增加。最常见的胰腺癌类型是胰管癌 腺癌（PDAC），其次是胰腺神经内分泌肿瘤（PNET）。胰腺癌通常是 由于转移扩散和治疗不足而致命。胰腺癌转移的驱动因素 癌症在很大程度上仍不清楚。迫切需要了解胰腺癌的生物学 转移并开发新的治疗策略。 我们是第一个报道透明质酸介导的运动异构体 B (RHAMMB) 的受体，但不是完整的 长度RHAMMA，促进PNET的转移。我们发现，在不同的剪接亚型中，RHAMMB 是 在人类 PDAC 中，RHAMMB 显着上调，并且较高的 RHAMMB 预示着 PDAC 的存活率较差。 然而，RHAMMB是否促进PDAC转移仍不清楚，将在本研究中确定。 提案工作。我们的初步数据表明 RHAMMB 过表达诱导 RhoA 信号传导、迁移、 PDAC 和 PNET 细胞系中的 3D 球体侵袭和脂滴 (LD) 生物发生，而 RHAMMB RhoA 信号传导的敲低或药理抑制会产生相反的效果。我们假设 RHAMMB 通过 RhoA 信号/LD 生物发生促进胰腺癌转移，并且该 RHAMMB /RhoA/LD 轴代表了一个新的治疗靶点。 为了检验这个假设，我们将使用多个实验系统，包括细胞系、原位肿瘤 异种移植、基因工程小鼠模型和患者来源的异种移植。研究结果将是跨 检查了。这项拟议研究的成功将建立 RHAMMB 促进的机制 胰腺癌转移并转化为治疗这种毁灭性的新治疗方法 癌症。