Dissertation

Oncogenic Mutations and Injury in the Mouse Liver

Alexander, William B

2017

Overview

Chronic injury and inflammation are among the most established determinants of cancer risk, and the myriad of factors that contribute to this association is an active area of investigation. A key aspect of injury is the consequent regenerative and proliferative response. Understanding the mechanisms which restrain these proliferative processes and how these controls can be bypassed may shed light on the processes that drive early cancer development. Focusing on the mouse liver as a model tissue, we sought to determine how common oncogenic mutations impact the ductular reaction, the liver’s response to injury and one of the earliest events in cholangiocarcinoma development. Here we identify, among the most commonly mutated genes in cholangiocarcinoma, a uniquely critical role for the tumor suppressor Smad4 in restraining proliferation of ductular reactive cells, the biliary/epithelial compartment of the ductular reaction. Experiments testing the tumor suppressive role of Smad4 in mouse liver revealed a complex role as a suppressor of hepatocellular carcinoma, cholangiocarcinoma, and biliary cyst development. Focusing on Smad4’s role in the ductular reaction, we identify an IGF activation signature in Smad4-perturbed ductular reactive cells and in SMAD4-mutant cancers that is potentially mediated by SMAD4-regulated transcription of IGF binding proteins, key inhibitors of IGF signaling. This study therefore importantly links a key tumor suppressive pathway to regulation of the injury response, thereby shedding light on the earliest events in cancer development. In a related project, we sought to understand the cellular origins of cholangiocarcinoma. Hepatocytes and biliary epithelial cells may both be potential cells of origin for cholangiocarcinoma, although the contexts in which this has been demonstrated are limited. For example, although hepatocytes can be cells of origin in the setting of active Notch signaling, a key driver of biliary differentiation, Notch pathway mutations are not common events in human cases; therefore, it remains unknown if common genetic lesions identified in human cholangiocarcinoma are sufficient to promote hepatocyte-derived cholangiocarcinoma. To shed light on these matters, we demonstrate that targeting Kras and Tp53 mutations, two of the most common mutations in human cholangiocarcinoma, to the SOX9+ biliary compartment promotes cholangiocarcinoma development. Similarly, targeting these mutations to the hepatocyte compartment can lead to cholangiocarcinoma development in the setting of injury. We further establish that Tp53 in particular has a critical function in restricting reprogramming of hepatocytes to biliary epithelial cells, a role that likely enables hepatocyte-derived iCCA when it is mutated. Finally, mirroring what has been observed in other biliary tract-derived models, we observed active Notch and Wnt signaling in our hepatocyte-derived model, suggesting hepatocyte-derived cholangiocarcinoma may have similar programming regarding these important targetable pathways. Understanding distinguishing biological features of hepatocyte-derived and biliary tract-derived cholangiocarcinoma may prove to have clinically relevant prognostic and therapeutic value.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biology / Genetics / Oncology
• ISBN: 9780355562651, 0355562650