GPCRs: novel targets in cancer-associated fibroblasts

GPCR：癌症相关成纤维细胞的新靶点

• 批准号: 8773037
• 负责人: PAUL A INSEL
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773037
• 关键词: Adenocarcinoma Cell; Biological; Biological Assay; Cancer Etiology; Cause of Death; Cell Proliferation; Cell Surface Proteins; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Collagen; Complement; Cyclic AMP; Desmin; Disease; Enzymes; Extracellular Matrix Proteins; Extracellular Space; Family; Family member; Fibroblasts; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; G-substrate; GTP Binding; GTP-Binding Proteins; Gene Expression; Gene Family; Genomics; Goals; Growth; Growth Factor; Human; Human Genome; Ligands; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane Proteins; Metabolism; Modeling; Molecular Weight; Mutation; Myofibroblast; Neoplasm Metastasis; Neurotransmitters; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological Processes; Production; Proteins; RNA Interference; Receptor Cell; Receptor Signaling; Relative (related person); Role; Second Messenger Systems; Signal Transduction; Smooth Muscle Actin Staining Method; Specificity; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Tumor Tissue; base; cell type; cytokine; functional genomics; gain of function; human disease; improved; interstitial; loss of function; member; migration; neoplastic cell; new therapeutic target; novel; oncology; outcome forecast; pressure; progenitor; public health relevance; receptor expression; response; second messenger; selective expression; stellate cell; therapeutic target; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), is the fourth leading cause of cancer death in the U.S. and has a 5-year survival of ~ 5%. A key contributor to this poor survival is the extensive desmoplasia (abundant fibrotic stroma) of PDAC, which can make it difficult to surgically remove the tumor and can limit access of therapeutic drugs to the tumor cells. Cancer-associated fibroblasts (CAFs), myofibroblast-like cells that produce extracellular matrix proteins, are responsible for the desmoplasia in PDAC. Pancreatic stellate cells (PSCs) and fibroblasts (PFs) are key progenitors of CAFs. Blocking the expression and activity of CAFs may be a means to improve the therapy and prognosis of PDAC. This proposal posits that G-protein-coupled receptors (GPCRs) are an important, understudied aspect of pancreatic CAFs and may be novel targets for the treatment of pancreatic cancer. GPCRs are the largest family of cell surface signaling receptors (3% of the human genome) and regulate many physiological processes. As plasma membrane proteins, GPCRs are accessible from the extracellular space; GPCRs are selectively expressed on cell types and tissues and show specificity in ligand interaction-factors that help explain why GPCRs are the targets for ~30% of current therapeutic agents albeit not in oncology. This R21 seeks to be transformative by identifying, quantifying and validating the expression of GPCRs by human pancreatic CAFs, and by assessing the therapeutic potential of GPCRs selectively expressed by CAFs (compared to PSCs and PFs). The project uses patient-derived pancreatic CAFs as a model and will use several genomic strategies: a GPCRomic approach to quantify gene expression of all non-chemosensory GPCRs, use of RNA interference knockdown GPCRs expressed by CAFs and identify the GPCRs that mediate key functional responses and gain-of-function studies by using normal pancreatic fibroblasts or pancreatic stellate cells and seeking to recapitulate the fibrotic phenotype of CAFs by enhancing expression of GPCRs in PSCs and PFs. The goal is to use genomic approaches to identify GPCRs as potential targets for the treatment of pancreatic cancer through their ability to block expression and pro-fibrotic activity of CAFs. The strategy that we will employ- GPCRomics of members of the GPCR gene family and gain of function and loss of function studies with members of this family in a human disease (in this case, in pancreatic cancer-associated fibroblasts)-is a novel one that should be readily applicable to CAFs in other cancers and to other disease settings. In addition, a further novel and clinically important aspect of this proposl is its initiation of efforts to test the idea that GPCRs on CAFs (in particular pancreatic CAFs) may be druggable targets for a disease that is in desperate need of new therapies.

简介(申请人提供)：胰腺癌，特别是胰腺导管腺癌(PDAC)，是美国第四大癌症死亡原因，5年生存率约为5%。造成这种低存活率的一个关键因素是PDAC广泛的促结缔组织增生(丰富的纤维间质)，这会使手术切除肿瘤变得困难，并可能限制治疗药物进入肿瘤细胞的途径。肿瘤相关成纤维细胞(CAF)是一种肌成纤维细胞样细胞，能产生细胞外基质蛋白，是PDAC中促结缔组织增生的原因。胰腺星状细胞(PSCs)和成纤维细胞(PFS)是CAF的主要祖细胞。阻断CAF的表达和活性可能是改善PDAC治疗和预后的手段之一。这一建议认为G蛋白偶联受体(GPCRs)是胰腺CAF的一个重要而未被研究的方面，并可能成为治疗胰腺癌的新靶点。GPCRs是最大的细胞表面信号受体家族(占人类基因组的3%)，调节着许多生理过程。作为质膜蛋白，GPCRs可以从细胞外空间获得；GPCRs选择性地表达在细胞类型和组织上，并在配体相互作用中显示出特异性-这有助于解释为什么GPCRs是目前约30%的治疗药物的靶标，尽管不是在肿瘤学中。R21试图通过识别、量化和验证人胰腺CAF的GPCRs的表达，并通过评估CAF选择性表达的GPCRs的治疗潜力(与PSCs和PFS相比)来寻求变革性。该项目使用患者来源的胰腺CAF作为模型，并将使用几种基因组策略：GPCR方法量化所有非化学敏感型GPCRs的基因表达，使用RNA干扰敲除CAF表达的GPCRs，通过使用正常胰腺成纤维细胞或胰星状细胞来确定介导关键功能反应和功能获得研究的GPCRs，并试图通过增强GPCRs在PSCs和PFS中的表达来概括CAF的纤维化表型。我们的目标是使用基因组方法，通过阻断CAF的表达和促纤维化活性，确定GPCRs作为治疗胰腺癌的潜在靶点。我们将采用的策略--GPCR基因家族成员的GPCRomics以及在人类疾病中对该家族成员进行的功能获得和功能丧失研究(在这种情况下，是在胰腺癌相关的成纤维细胞中)--是一种新的策略，应该很容易适用于其他癌症和其他疾病环境中的CAF。此外，这项提议的另一个新颖和临床重要的方面是它开始努力测试CAF(特别是胰腺CAF)上的GPCR可能是一种迫切需要新疗法的疾病的可用药靶点的想法。