FGF10 is a secreted growth factor that is critical for pancreatic development. FGF10 has significant therapeutic importance as it is required for directing embryonic stem cells to a pancreatic cell fate and FGF10 signaling increases the invasiveness of pancreatic cancer. While the biological and clinical relevance of FGF10 is established, the intracellular signaling cascades triggered by FGF10 are vastly understudied, hindering its optimal use for therapeutic methods. We identified several novel aspects about the signaling mechanism FGF10. For example, we characterized several new transcription factors that were upregulated by FGF10 in the embryonic pancreas. We also found that FGF10 controls progenitor maintenance in multiple endodermal organs. Our genomics studies revealed that the signaling network of FGF10 involves immediate control of MAPK and PI3K signaling, which, in turn, control the Notch and β-catenin pathways. These pathways are involved in pancreatic tumorigenesis and regeneration and are linked to stem cell maintenance in various organs. Our studies suggest that FGF10 is a critical determinant of the endodermal stem cell state. In this proposal, we will functionally test the importance of the MAPK and PI3K pathways activated by FGF10 signaling in the pancreas using in vivo and ex vivo models. In previous studies of our FGF10 overexpression model, we identified two novel ETS-family transcription factors, Etv4 and Etv5, activated by phosphorylation via MAPK signaling. We will test the hypothesis that Etv4 and Etv5 are critical for FGF10 signaling using gene ablation studies of these factors. We will identify the target gene sets of Etv4 and Etv5. We also observed that FGF10 signaling upregulated p63, a transcription factor linked to stem cell maintenance. As p63 has an essential role in the development of stratified epithelial tissues, this factor may have a similar function in maintaining the initial stratified state of the budding pancreas. We hypothesize that FGF10 signaling activates p63 to promote selfrenewal of the pancreatic progenitors. The goal of our proposal is to characterize the intracellular signaling pathways activated by FGF10 within the developing pancreas. Our experimental approach will elucidate how FGF10 signaling regulates crucial cell intrinsic factors via the PI3K and MAPK pathways. Knowledge of these signaling cascades will significantly enhance our understanding of how the downstream components of FGF10 signaling influence processes such as cellular proliferation and differentiation. Such information about FGF10 signaling will directly impact the clinical disciplines of regenerative medicine for diabetes and treatment modalities for pancreatic cancer. Our study will also impact the fields of gastrointestinal pathobiology and regenerative medicine as we previously found that the FGF10 pathway and its signaling components are conserved throughout the developing gut.
We will here investigate the molecular mechanism of the FGF10 signaling pathway in pancreatic development. We will focus on the relative roles of MAPK and PI3K pathways controlled by FGF10, and how these branches regulate FGF10 target genes via transcriptional regulators p63 and Etv4/5. These studies are significant in relation to cell therapy for diabetes, pancreatic cancer and organ regeneration.
| Nyeng, Pia; Bjerke, Maureen Ann; Norgaard, Gitte Anker et al. (2011) Fibroblast growth factor 10 represses premature cell differentiation during establishment of the intestinal progenitor niche. Dev Biol 349:20-34 |
| Rovira, Meritxell; Scott, Sherri-Gae; Liss, Andrew S et al. (2010) Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A 107:75-80 |
