Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the United States. In our recent reports, we demonstrated tumor promoting role of Sprouty2, an endogenous suppressor of receptor tyrosine kinase (RTK)/ Mitogen Activated Protein Kinase (MAPK) signaling pathways in colorectal cancer (CRC). In order to establish in vivo role of Sprouty2 in cancer we recently generated Sprouty2F/F mouse in our laboratory. The objectives of this RO3 application are to characterize the model and study the effect of embryonic (Sprouty2F/F-Villin Cre) and postnatal (Sprouty2F/F-Villin CreERT2) deletion of Sprouty2 on CRC progression. Our rationale for these studies is that establishing in vivo role of Sprouty2 gene in CRC would allow us to submit a mechanistic RO1 application. In vitro studies from our laboratory utilizing cell culture models, orthotopic and metastasis mouse models demonstrated oncogenic potential of Sprouty2 in CRC. In preliminary studies, we also established that TAT dependent Sprouty2 protein transduction or Sprouty2 stable transfection favors cancer phenotype. On the contrary suppression of Sprouty2 supports epithelial features in cancer cells and murine embryonic fibroblasts (MEFs) obtained from Sprouty2F/F-Villin CreERT2 mouse. However, requirement of Sprouty2 in CRC progression in vivo is not established. Effect of embryonic and postnatal Sprouty2 deletion in Sprouty2F/F-Villin Cre (embryonic deletion) and Sprouty2F/F-Villin CreERT2 mouse (tamoxifen dependent postnatal deletion), respectively, will be studied during AOM/DSS induced colonic carcinogenesis. We will also examine effect of Sprouty2 deletion in vivo on intestinal cell differentiation and lineage by utilizing both mice groups. To our knowledge, this is the first study to demonstrate the effect of in vivo deletion of SPRY2 on CRC progression and intestinal cell lineage. We have established our hypothesis based on our past and recent publications. The proposed study is a multi-prong approach to prepare us for a RO1 application.
Our laboratory discovered that Sprouty2 gene is a putative oncogene in colorectal cancer. To validate the role of Sprouty2 in colorectal cancer we have recently generated a new intestinal specific gene deletion mouse model. We will characterize this mouse model for mechanistic studies. These studies are required to propose a RO1 application.
