Determining the Role of PTEN/AKT Signaling in Extrahepatic Cholangiocarcinoma Using a Novel Genetic Mouse Model
Developmental Research Program Overview
Cholangiocarcinoma (CCA) is an aggressive cancer that forms in the cells that line the bile duct. The only treatment options include aggressive chemotherapy, radiation or surgery. Cholangiocarcinoma can start either from the cells that line the bile duct within the liver (intrahepatic) or outside the liver (extrahepatic). Extrahepatic cholangiocarcinoma accounts for more than 90% of all CCA cases. There's no mouse model capable of studying the disease.
In this work in the Developmental Research Program in the Mayo Clinic Hepatobiliary SPORE, we have two major goals: One is to create a genetic mouse model for studying extrahepatic CCA, and the other is to study how the PTEN-AKT signaling pathway affects the progression of inflammation to cancer in CCA. This latter goal is important because genetic changes in the PTEN-AKT pathway are found in more than 80% of cholangiocarcinoma cases.
An abnormal increase in PI3K/AKT signaling is observed in more than 80% of CCA cases. PTEN negatively regulates the PI3K/AKT pathway. Therefore, PTEN deletion results in constant activation of the PI3K/AKT pathway.
We recently were able to delete the PTEN gene in mouse bile duct cells. In these PTEN-deleted mice, enlargement of the extrahepatic bile duct developed as early as one month after birth. Microscopically, we were able to see inflammation, fibrosis, ductal cell proliferation and precancerous lesions. The phenomenon mimics what is seen in human chronic cholangitis, a risk factor for CCA. In contrast to the obvious phenotype seen in the bile duct, PTEN deletion in the pancreatic duct did not lead to disease. We reasoned that bile salt stimulation is involved in extrahepatic CCA.
This new genetic mouse model is helping us test our central hypothesis that bile salts activate the PTEN-AKT signaling pathway in bile duct cells to initiate a disease spectrum from cholangitis to CCA. In specific aim 1, we are studying the roles of the PTEN-AKT pathway in disease development from inflammation through neoplasia during extrahepatic CCA formation. In specific Aim 2, we are testing whether bile salts trigger cell proliferation, inflammation and fibrosis through the PTEN-AKT signaling pathway.
This study is crucial because a CCA mouse model will help us understand how this disease develops in humans and will allow us to test new therapies.