Role of FGFR1 signaling in distinct cell lineages in prostate cancer progresssion

FGFR1 信号在不同细胞谱系中在前列腺癌进展中的作用

• 批准号: 8334481
• 负责人: Michael M Ittmann
• 金额: $ 67.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334481
• 关键词: Affect; Animal Model; Biological; Biological Markers; Biology; Carcinoma; Cell Lineage; Cells; Clinical; Drug Delivery Systems; Ectopic Expression; Epithelial; Epithelium; Evaluation; Fibroblast Growth Factor Receptor 1; Genetic Recombination; Genetically Engineered Mouse; Glean; Human; Knock-out; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Modeling; Molecular; Neoplasm Metastasis; Outcome; Patients; Primary Neoplasm; Principal Investigator; Property; Prostate; Reagent; Relative (related person); Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Stem cells; Testing; Tissue Microarray; Tissue Model; Transgenic Model; Work; base; cancer initiation; design; experience; human tissue; improved; in vivo; knowledge base; mouse model; novel; programs; tumor growth; tumor progression

DESCRIPTION (provided by applicant): This application focuses on understanding the fundamental biology induced by ectopic expression and activation of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. Our previous studies utilizing genetically engineered mouse models (GEMMs) demonstrated that ectopic FGFR1 signaling in prostate epithelium results in an epithelial-mesenchymal transition (EMT)-associated carcinoma, and conditional knockout of FGFR1 results in decreased primary tumor growth. These studies also showed that ectopic FGFR1 is linked to metastasis. It is now clear that FGFR1 is ectopically present in human PCa, as well, and this has been suggested to mediate EMT, invasion and metastasis. We will now probe several interrelated key questions in order to further define FGFR1's role in cancer initiation, promotion of an inductive microenvironment, and progression to metastases. Our proposed study involves novel transgenic models, cell recombination models, and evaluation of human tissue specimens. This integrative approach, by design, takes advantages of our combined strengths and experiences in building novel transgenic models, probing signaling pathways, and evaluating extensive human tissue sets relative to clinical outcomes. Completion of the proposed study will allow us to understand whether FGFR1activation in epithelial progenitor cells produces cancer with different properties relative to activation in more differentiated, prostate luminal cells, and how these putatively distinct lesions respond to different drugs targeting the FGFR1 signaling axis. The role of FGFR1 signaling in inducing EMT and cell invasion and metastasis will be probed. Moreover, how key FGFR1-activated signaling pathways program a "reactive stroma" microenvironment, and how this biology affects tumor progression will be assessed. To place this work into a clinical perspective, new biological discoveries gleaned from in vivo mouse models will be validated using human tissue arrays, comprising a large set of patient samples. This will help determine the correlation between ectopic FGFR1 expression with cancer grade and clinical outcome. It is anticipated that this study will provide a deeper, molecular understanding of PCa, characterize key animal and tissue models and build a broad knowledge base from which to build improved strategic approaches to targeting the FGFR1 signaling axis therapeutically.

描述（由申请人提供）：本申请重点了解前列腺癌（PCa）进展中成纤维细胞生长因子受体 1（FGFR1）的异位表达和激活所诱导的基础生物学。我们之前利用基因工程小鼠模型 (GEMM) 进行的研究表明，前列腺上皮中的异位 FGFR1 信号传导会导致上皮间质转化 (EMT) 相关癌，而 FGFR1 的条件性敲除会导致原发性肿瘤生长减少。这些研究还表明异位 FGFR1 与转移有关。现在已经清楚，FGFR1 也异位存在于人类 PCa 中，并且这已被认为可以介导 EMT、侵袭和转移。我们现在将探讨几个相互关联的关键问题，以进一步确定 FGFR1 在癌症发生、诱导微环境的促进和转移进展中的作用。我们提出的研究涉及新型转基因模型、细胞重组模型和人体组织标本的评估。这种综合方法在设计上利用了我们在构建新型转基因模型、探测信号通路以及评估与临床结果相关的广泛人体组织集方面的综合优势和经验。完成拟议的研究将使我们能够了解上皮祖细胞中的 FGFR1 激活是否会产生相对于分化程度更高的前列腺腔细胞中的激活具有不同特性的癌症，以及这些假定的不同病变如何对针对 FGFR1 信号轴的不同药物做出反应。将探讨 FGFR1 信号传导在诱导 EMT 以及细胞侵袭和转移中的作用。此外，还将评估关键的 FGFR1 激活信号通路如何编程“反应性基质”微环境，以及这种生物学如何影响肿瘤进展。为了将这项工作纳入临床视角，从体内小鼠模型中收集到的新生物学发现将使用包含大量患者样本的人体组织阵列进行验证。这将有助于确定异位 FGFR1 表达与癌症分级和临床结果之间的相关性。预计这项研究将提供对 PCa 更深入的分子理解，表征关键的动物和组织模型，并建立广泛的知识库，从中建立改进的战略方法来靶向 FGFR1 信号轴治疗。