Determining the Role of TCF7L2 in Pancreatic Cancer

Pancreatic cancer is one of the most aggressive and deadly cancers.  Early detection and screening is difficult because pancreatic cancer is largely asymptomatic during its early stages. The Wnt/b-catenin signaling pathway is dysregulated pancreatic ductal adenocarcinoma and other cancers.  The canonical Wnt/b-catenin signaling cascade results in the regulation of Wnt target genes through a TCF/LEF transcription factor. One TCF/LEF family member, TCF7L2, is highly up regulated in several human cancers and numerous studies have linked TCF7L2 with the Wnt/β-catenin pathway. It is not clear whether TCF7L2 functions as an oncogene or as a tumor suppressor as different studies have suggested TCF7L2 involvement in both roles. I will determine if TCF7L2 functions as a tumor suppressor or oncogene in pancreatic cancer.  Pancreatic cancers commonly develop chemoresistance creating a need for specific inhibitors of signaling pathways dysregulated in cancers.  One inhibitor of the Wnt/ b-catenin pathway, ICG-001, has been shown to disrupt the CBP/ b-catenin interaction and favor the formation of a p300/b-catenin interaction. This switch in complex formation is thought to promote activation of Wnt genes involved in cell differentiation, while suppressing Wnt target genes involved in stem cell maintenance.   Though ICG-001 reduces tumorigenicity, the exact molecular mechanism by which this occurs in pancreatic cancers is not known.  It is critical to better characterize the mechanism of ICG-001 as it is being tested in patients.  I will determine the role of TCF7L2 in the suppression of tumorigenicity by ICG-001 in pancreatic cancer cells and further elucidate the mechanism of ICG-001 function.