"A Forward Genetic Screen to Identify Functionally Important Colon Cancer Oncogenes and Tumor Suppressor Genes"
Colorectal cancer (CRC) arises secondary to the accumulation of gene mutations and epigenetic alterations in colon epithelial cells that ultimately transform the normal cell into a cancer cell. One of the most commonly deregulated signaling pathways in CRC is the transforming growth factor ß (TGF-ß) pathway. TGF-ß is a multifunctional cytokine that regulates the function of epithelial cells, mediating its effects by binding to a heteromeric receptor composed of the type I and type II TGF-ß receptors, TGFBR1 and TGFBR2. TGFBR2 is an essential component of the TGF-ß signaling pathway, and the gene for TGFBR2 is mutated in 30% of CRCs. Of importance, the consequences of the loss of TGF-ß signaling in CRC are determined by the concurrent mutations in the tumor cell and these concurrent mutations have a profound effect on the way cells respond to TGF-ß, which can vary from tumor suppressing effects to oncogenic effects. To date, most of the mutations that cooperate with the deregulated TGF-ß signaling pathway remain unknown. Gaining a better understanding of the functionally relevant mutations that cooperate with TGF-ß signaling alterations in CRC will lead to insights into more effective and specifically targeted treatment options. However, given the thousands of mutations found in each cancer genome, identification of the functionally important genes presents a significant challenge. For that reason we propose to employ an innovative forward genetic screen using the recently developed Sleeping Beauty transposon mouse model (Rosa26-LsL-SB11;T2/Onc2) to identify novel genes that cooperate with TGFBR2 inactivation to affect CRC formation.