Abstract 3287: Intra- and intercellular Wnt pathway induction synergistically accelerates FGFR1-mediated prostate tumorigenesis

Cancer growth and metastasis requires proliferation, cell migration, and stromal remodeling, functions also found during organogenesis and wound repair. The fibroblast growth factor (FGF) and canonical Wnt/β-catenin signaling pathways are two pathways central to these functions. FGFs and their receptors (FGFRs) are expressed in most tissues and play pivotal roles in development, wound healing and neovascularization, and are also upregulated in many solid cancers, including prostate, mammary, renal, kidney, bladder, and testicular tumors. We previously demonstrated in the JOCK1 (juxtaposition of CID and kinase) prostate cancer (PCa) mouse model that chemically induced dimerization (CID) of FGFR1 signaling in the prostate is sufficient for tumor initiation and early tumor maintenance and prolonged (42 weeks) FGFR1 activation results in PCa with distant metastasis. The Wnt pathway is also vital for proper embryogenesis and homeostasis of adult tissues by regulating stem cell self-renewal, pluripotency, and differentiation in several tissues, including colon, hair shaft, and chondrocyte stem/progenitor cells. The uncontrolled activation of this important stem pathway is also associated with various cancers, including colon, breast and prostate. Recently, we have discovered that induced crosslinking of the Wnt co-receptor LRP5 is sufficient to induce canonical Wnt signaling and nuclear localization of β-catenin. We subsequently developed two novel mouse models where Wnt can be specifically activated in the prostate epithelium, Pro-Cat (prostate-targeted inducible β-catenin), or in virtually every tissue sub-layer, Ubi-Cat (ubiquitously expressed inducible β-catenin). Consistent with previous literature, induced Pro-Cat mice never progressed beyond prostatic hyperplasia, however, after a year of pathway induction, 2 out of 6 Ubi-Cat mice developed adenocarcinoma, indicating a yet unexplored role for stromal Wnt signaling in tumorigenesis. In order to delineate possible crosstalk and synergism between FGF and Wnt pathways, we bred JOCK1 mice unto Pro-Cat and Ubi-Cat transgenic lines. Both Pro-Cat/JOCK1 and Ubi-Cat/JOCK1 mice developed widespread hyperplasia, high-grade PIN and adenocarcinoma with an extensive reactive stroma by 24 weeks of CID injections. Fascinatingly, Pro-Cat/JOCK1 mice do not continue to progress beyond the timeline established by JOCK1 induction alone whereas Ubi-Cat/JOCK1 mice continue to progress to advanced transitional sarcomatoid lesions. These results suggest that intracellular crosstalk between Wnt and FGFR1 in the epithelia is sufficient to accelerate tumor initiation, however accelerated progression requires intercellular crosstalk between the stroma and the epithelia. Additional experiments necessary to definitively implicate the stroma in accelerated tumorigenesis are underway and will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3287. doi:1538-7445.AM2012-3287