Pancreatic cancer is one of the leading causes of cancer related deaths worldwide. While some strides have been made in treating this disease, the five-year survival is a dismal 7%. One reason for this abysmal rate is that many patients do not present symptoms until they have late stage cancer and metastases to other organs. Although early progression of pancreatic cancer is well characterized - activating mutations in KRAS and subsequent loss of several tumor suppressors - the genes which contribute to metastasis in pancreatic cancer are not as well characterized. Several genome wide sequencing endeavors have been performed to elucidate the genes responsible for pancreatic cancer metastasis, and there is a growing consensus that dysfunction of the WNT/B-Catenin signaling pathway and disruption of apoptosis contribute to this progression however the underlying mechanisms are unknown. Other efforts to illuminate novel genes that drive metastasis have utilized transposon-mediated insertional mutagenic screens in mice. In one screen, a gene with one of the highest rates of mutation was FOXP1, where transposon insertion caused an increase in FOXP1 expression within tumors. Validating this discovery, RNAi-mediated depletion of FOXP1 mRNA in an orthotopic mouse tumor model resulted in fewer metastases as compared to mice with tumors expressing FOXP1. FOXP1 also directly negatively regulates E-Cadherin, a marker of the epithelial to mesenchymal transition (EMT) that is important for metastatic progression. Indeed, high FOXP1 mRNA expression levels in pancreatic cancer tumors has correlates with a poorer prognosis in patients. The work proposed here will establish FOXP1 as a driver of metastasis in pancreatic cancer and evaluate its potential as a therapeutic target.
Pancreatic cancer is one of the leading causes of cancer related deaths, and patient prognosis is poor due to late stage detection. Poorly understood cell signaling pathways drive the progression and metastatic potential of pancreatic cancer. The goal of this proposal is to identify novel cell signaling proteins that promote metastatic tumor progression with the hope of targeting these proteins as future therapeutics for pancreatic cancer.
