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.

项目摘要/摘要 胰腺导管腺癌（PDA）是一种侵略性和致命的癌症，其特征是胶原蛋白 密集的微环境。胶原蛋白的过量生产和随后的纤维化是 近年来学习；但是，这一突出特征在PDA中的影响尚无定论。扩展 如在慢性炎症（胰腺炎）中所见，胰腺损伤导致促纤维胶原蛋白的反应 这促进了一个称为腺泡 - 导管化生的初始过程（ADM）。 ADM是上皮的事件 腺泡细胞转分化成具有祖细胞特征的管状细胞，被认为是前体 在有致癌性Kras的情况下向PDA致PDA。因此，研究腺泡细胞之间的相互作用 使用胶原蛋白密度的基质隔室可能会在激活ADM的激活和 PDA的逐步发展。 新的初步证据表明盘状结构域受体2（DDR2），一种独特的受体酪氨酸激酶 （RTK）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 日期，尚未研究DDR2的激活和随后的细胞内信号传导 胰腺疾病的背景。 DDR2是PDA研究的可能候选者 胶原蛋白过量生产及其作为RTK的性质，可适应药物干预。这些事实 该提案将检验以下假设：DDR2激活对于促进信号是必要的 PDA进展和转移所需的肿瘤细胞和基质 Will：1。）检验以下假设：PDA的发展需要肿瘤细胞中的DDR2。 2.）测试 假设肿瘤细胞和成纤维细胞中的DDR2激活是侵袭和转移需要的 PDA。为了实现这些特定目的，人类细胞系和基因工程的鼠标模型将是 用于进行适当的体外和体内实验，以研究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 将DDR2识别为患者的诊断和治疗靶点的总体未来目标。提议 本申请中的研究遵循露丝·柯希斯坦国家研究服务奖的目标 （NRSA）用于确定新方法并生成的单个单个奖学金奖学金（父级F31） 促进癌症研究进展的科学思想。