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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRLB-Q (M1))
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Marks, Cheryl L
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Baylor College of Medicine
Schools of Medicine
United States
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Kwon, Oh-Joon; Zhang, Li; Wang, Jianghua et al. (2016) Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J Clin Invest 126:2626-41
Wang, Wei; Dong, Bingning; Ittmann, Michael M et al. (2016) A Versatile Gene Delivery System for Efficient and Tumor Specific Gene Manipulation in vivo. Discoveries (Craiova) 4:
Ayala, Gustavo; Frolov, Anna; Chatterjee, Deyali et al. (2015) Expression of ERG protein in prostate cancer: variability and biological correlates. Endocr Relat Cancer 22:277-87
Kwon, Oh-Joon; Valdez, Joseph M; Zhang, Li et al. (2014) Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat Commun 5:4416
Kwon, Oh-Joon; Zhang, Li; Ittmann, Michael M et al. (2014) Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc Natl Acad Sci U S A 111:E592-600
Zhang, B; Chen, H; Zhang, L et al. (2014) A dosage-dependent pleiotropic role of Dicer in prostate cancer growth and metastasis. Oncogene 33:3099-108
Carstens, Julienne L; Shahi, Payam; Van Tsang, Susan et al. (2014) FGFR1-WNT-TGF-? signaling in prostate cancer mouse models recapitulates human reactive stroma. Cancer Res 74:609-20
Ittmann, Michael; Huang, Jiaoti; Radaelli, Enrico et al. (2013) Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res 73:2718-36
Feng, Shu; Dakhova, Olga; Creighton, Chad J et al. (2013) Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res 73:2551-62
Xin, L (2013) Cells of origin for cancer: an updated view from prostate cancer. Oncogene 32:3655-63

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