ZIA BC 005093 (ZIA) | |||
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Title | Growth/Differentiation Factors in Organogenesis | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Perantoni, Alan | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $822,793 | Project Dates | 10/01/1978 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (5.0%) Childhood Cancers (50.0%) |
Kidney Cancer (50.0%) Kidney Disease (90.0%) Urinary System (90.0%) Wilm's Tumor (40.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Development and Characterization of Model Systems |
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Abstract | |||
The Renal Differentiation and Neoplasia Section studies inductive signaling in tissue development/morphogenesis and, in parallel, its dysregulation in tumorigenesis with emphasis on the ligands that mediate normal tissue interactions and the pathways and targets that are activated in response to signaling. Our focus has been on development of the urogenital tract, which features reciprocal interactions between two distinct mesodermal progenitors, highly coordinated tissue movements, mesenchymal-epithelial transition (MET), integration of structures from different lineages, reiterative cycles of development, and a tumor that caricatures nephrogenesis. More specifically we are interested in the signaling mechanisms that direct metanephric mesenchyme (MM) to convert to the epithelia of the nephron. Wilms tumor (WT) is characterized by an expanded blastemal/progenitor population with a restricted capacity for epithelial conversion (MET). It is our long-term goal to identify targets on which WT cells depend for survival or dysregulated signaling that can be reprogrammed to allow tumor cells to differentiate to a more benign phenotype. Last year we determined that the cytokine leukemia inhibitory factor (LIF) maintains and expands the nephronic stem cell population in culture. It functions principally through activation of STATs 1, 3 and 5 and up regulates the expression of several renal stem cell markers, e.g., Six2 and Pax2. Mechanistically, we have now found that LIF stimulates JNK activation, which induces MM proliferation and enhances cell competence to differentiate. Also, cells treated with a Rho kinase inhibitor (ROCKi) in addition to LIF retain their ability to undergo MET in culture, thus producing a powerful tool for studying this differentiation in culture and opening the possibility of regenerating renal tissues. An investigation into the mechanism(s) mediated by LIF/ROCKi in these cells revealed that our conditions facilitate the nuclear localization of Yes-associated protein (YAP), a transcriptional co-activator and component of the Hippo signaling pathway. Furthermore, silencing Yap gene expression by siRNA knockdown in MM cells decreased the expression of progenitor markers and increased levels of MET markers, suggesting that YAP maintains MM cells in an undifferentiated state. Since YAP interacts with Tead transcription factors, we also determined that canonical Yap signaling through Tead activation is required for YAP-dependent transcription and MM progenitor cell maintenance. This culture system of MM provides unique opportunities to comprehensively address key mechanisms involved in renal progenitor maintenance and differentiation. Furthermore, these studies support the hypothesis that Yap plays an important role not only in kidney development but also in Wilms tumorigenesis, where we have reported that Yap and surprisingly pYap are both nuclear localized in the blastemal component of these tumors. Our work on the role of STATs in the developing metanephros has slowed due to problems with the acquired mouse line. Accordingly, we are addressing the technical challenge. Regardless, because of the considerable significance of our observed bone phenotype, we continue to investigate the role of Stat3 in this tissue. We have determined that the conditional loss of Stat3 causes a phenotype typical of two bent bone disorders, campomelic dysplasia and Stuve-Wiedemann syndrome. Using conditional loss-of-function (LOF) mouse models, a preliminary assessment of a LOF mutant for Stat3 has revealed extensive defects in the skeletal system, which appear to tie these two congenital abnormalities together. Specifically, we have found that Stat3 is required for maintenance of the trabecular bone, and the loss of Stat3 results in shortening of the long bones and their improper mineralization. Signatures consistent with interrupted endochondral bone formation were evident in the expansion of hypertrophic chondrocytes and the observ" |