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

描述(申请人提供)：本申请侧重于了解前列腺癌(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，前列腺上皮中异位的FGFR1信号导致上皮-间充质转化(EMT)相关癌，条件基因敲除FGFR1导致原发肿瘤生长减少。这些研究还表明，异位FGFR1与肿瘤转移有关。现已清楚的是，FGFR1在人前列腺癌中也是异位存在的，这被认为是介导EMT、侵袭和转移的媒介。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的S在肿瘤启动、诱导微环境促进和转移进展中的作用。我们提出的研究涉及新的转基因模型、细胞重组模型和对人体组织标本的评估。通过设计，这种综合方法利用了我们在构建新的转基因模型、探索信号通路和评估相对于临床结果的广泛人体组织集方面的优势和经验。拟议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更高的前列腺腔细胞中的激活相比具有不同性质的癌症，以及这些假定不同的病变对针对FGFR1信号轴的不同药物有何反应。我们将探讨FGFR1信号在诱导EMT和细胞侵袭转移中的作用。此外，将评估关键的FGFR1激活的信号通路如何规划“反应性间质”微环境，以及这种生物学如何影响肿瘤进展。为了将这项工作投入临床，将使用由大量患者样本组成的人体组织阵列来验证从活体小鼠模型中收集到的新的生物学发现。这将有助于确定异位FGFR1表达与肿瘤分级和临床结果之间的相关性。预计这项研究将提供对PCA的更深层次的分子理解，描述关键的动物和组织模型，并建立广泛的知识基础，以此为基础建立针对FGFR1信号轴的改进的治疗策略。

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.