Determining the Role of Discoidin Domain Receptor 2 in the Pathogenesis of Pancreatic Ductal Adenocarcinoma

确定盘状蛋白结构域受体 2 在胰腺导管腺癌发病机制中的作用

• 批准号: 10215381
• 负责人: Jeanine Ruggeri
• 金额: $ 0.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-06-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215381
• 关键词: 3-Dimensional; Achievement; Acinar Cell; Adhesions; Adult; Affect; Binding; Biochemical; CRISPR/Cas technology; Cancer Etiology; Cell Line; Cell Proliferation; Cells; Cessation of life; Characteristics; Chronic; Clinical; Coculture Techniques; Collagen; Data; Development; Diagnosis; Diagnostic; Disease; Duct (organ) structure; Early Diagnosis; Epithelial; Epithelial Cells; Epithelium; Event; Fellowship; Fibrillar Collagen; Fibroblasts; Fibrosis; Future; Genetically Engineered Mouse; Human; Human Cell Line; Immunohistochemistry; Implant; In Vitro; Individual National Research Service Award; Inflammation; Intervention; Knock-out; Knockout Mice; Left; Lesion; Ligands; Malignant Neoplasms; Mediating; Mediation; Mesenchymal; Metaplasia; Methods; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Neoplasms; Non-Small-Cell Lung Carcinoma; Oncogenic; Operative Surgical Procedures; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatitis; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Play; Process; Production; Receptor Protein-Tyrosine Kinases; Role; Signal Transduction; Stains; Stromal Cells; Survival Rate; Symptoms; System; Testing; Therapeutic; Tissue Microarray; Tumor-Derived; anticancer research; base; cancer cell; cell motility; cell stroma; discoidin domain receptor 2; epithelial to mesenchymal transition; experimental study; in vivo; innovation; insight; malignant breast neoplasm; mortality; mouse model; mutant; neoplastic; neoplastic cell; novel; pancreas development; pancreatic cancer cells; pancreatic tumorigenesis; pre-doctoral; progenitor; prognostic value; response; targeted treatment; therapeutic target; transdifferentiation; tumor microenvironment; wound healing

PROJECT SUMMARY/ABSTRACT Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive and lethal cancer characterized by a collagen- dense microenvironment. The overproduction of collagen and the subsequent fibrosis that follows has been studied in recent years; however, the impact of this prominent feature in PDA is left inconclusive. Extended pancreatic injury, as seen in chronic inflammation (pancreatitis), results in a pro-fibrotic collagen-rich response that promotes an initial process called acinar-ductal metaplasia (ADM). ADM is an event in which the epithelial acinar cells transdifferentiate into duct-like cells with progenitor characteristics and is thought to be a precursor to PDA in the presence of oncogenic Kras. Therefore, investigating the interactions between the acinar cells with the collagen-dense stromal compartment may offer a point of intervention in the activation of ADM and the gradual development of PDA. New preliminary evidence suggests Discoidin Domain Receptor 2 (DDR2), a unique receptor tyrosine kinase (RTK) that signals in response to binding to its collagen ligand may play a role in the development of PDA. To date, the activation of DDR2 and the subsequent intracellular signaling that follows has not been studied in the context of pancreatic diseases. DDR2 is a probable candidate in the study of PDA due to the dominant collagen overproduction and its nature as an RTK that is amenable to drug intervention. With these facts in place, this proposal will test the hypothesis that DDR2 activation is necessary to promote signaling between tumor cells and stroma that is required for the progression and metastasis of PDA The following specific aims will: 1.) Test the hypothesis that DDR2 in tumor cells is required for the development of PDA. 2.) Test the hypothesis that DDR2 activation in tumor cells and fibroblasts is required for the invasion and metastasis of PDA. To accomplish these specific aims, human cell lines and genetically engineered mouse models will be used to perform the appropriate in vitro and in vivo experiments to study PDA progression and metastasis. The results from these innovative studies will establish the role of DDR2 in the progression of PDA with the overall future aim of identifying DDR2 as a diagnostic and therapeutic target for patients. The proposed studies in this application follow the objectives of the Ruth L. Kirschstein National Research Service Award (NRSA) for Individual Predoctoral Fellowship (Parent F31) in determining novel methods and generating scientific ideas to promote the advancement of cancer research.

项目概要/摘要 胰腺导管腺癌 (PDA) 是一种侵袭性和致命性癌症，其特征是胶原蛋白- 致密的微环境。胶原蛋白的过量产生以及随之而来的纤维化已被证实 近年来学习；然而，PDA 中这一突出功能的影响尚无定论。扩展 慢性炎症（胰腺炎）中所见的胰腺损伤会导致富含促纤维化胶原蛋白的反应 促进称为腺泡导管化生 (ADM) 的初始过程。 ADM 是上皮细胞发生的事件 腺泡细胞转分化为具有祖细胞特征的导管样细胞，被认为是前体细胞 在存在致癌 Kras 的情况下将其转化为 PDA。因此，研究腺泡细胞之间的相互作用 胶原蛋白致密的基质隔室可能为 ADM 的激活和 PDA的逐步发展。 新的初步证据表明盘状蛋白结构域受体 2 (DDR2) 是一种独特的受体酪氨酸激酶 （RTK）表明，响应与其胶原配体结合的信号可能在 PDA 的发展中发挥作用。到 迄今为止，DDR2 的激活以及随后的细胞内信号传导尚未在 胰腺疾病的背景。 DDR2 是 PDA 研究中的一个可能的候选者，因为它占主导地位。 胶原蛋白过量产生及其作为 RTK 的性质，易于药物干预。有了这些事实 该提案将测试以下假设：DDR2 激活对于促进之间的信号传输是必要的 PDA进展和转移所需的肿瘤细胞和基质 以下具体目标 将： 1.) 检验肿瘤细胞中的 DDR2 对于 PDA 的发展是必需的这一假设。 2.) 测试 假设肿瘤细胞和成纤维细胞中的 DDR2 激活是肿瘤细胞侵袭和转移所必需的 掌上电脑。为了实现这些具体目标，人类细胞系和基因工程小鼠模型将被 用于进行适当的体外和体内实验来研究 PDA 进展和转移。 这些创新研究的结果将确定 DDR2 在 PDA 进展中的作用 未来的总体目标是将 DDR2 确定为患者的诊断和治疗靶点。拟议的 本申请中的研究遵循 Ruth L. Kirschstein 国家研究服务奖的目标 （NRSA）个人博士前奖学金（家长 F31）确定新方法并生成 推动癌症研究进步的科学理念。