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

描述（由申请人提供）：本申请的重点是了解由成纤维细胞生长因子受体1 （FGFR1）异位表达和激活在前列腺癌（PCa）进展中诱导的基础生物学。我们之前利用基因工程小鼠模型（GEMMs）的研究表明，前列腺上皮中的异位FGFR1信号导致上皮-间质转化（EMT）相关的癌，并且有条件地敲除FGFR1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。现在很清楚，FGFR1也异位存在于人类PCa中，并且已被认为介导EMT、侵袭和转移。我们现在将探讨几个相关的关键问题，以进一步确定FGFR1在癌症起始、诱导微环境的促进和转移进展中的作用。我们提出的研究包括新的转基因模型、细胞重组模型和人体组织标本的评估。这种综合方法，通过设计，利用我们在建立新型转基因模型，探测信号通路和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。这项研究的完成将使我们能够了解上皮祖细胞中的FGFR1激活是否会产生与分化程度更高的前列腺腔细胞中的激活不同性质的癌症，以及这些假定的不同病变如何对靶向FGFR1信号轴的不同药物做出反应。FGFR1信号在诱导EMT和细胞侵袭转移中的作用将被探讨。此外，fgfr1激活的关键信号通路如何规划“反应性基质”微环境，以及这种生物学如何影响肿瘤进展将被评估。为了将这项工作纳入临床研究，从体内小鼠模型中收集到的新的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表达与癌症级别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，从而建立改进的靶向FGFR1信号轴的治疗策略。

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.