Targeting Bistable Stem Cell States in Response to APC Loss in FAP
Christopher Legner, PhD
Chair, Department of Biomedical Sciences
Member, Institute for Regenerative Medicine, Perelman School of Medicine
Member, NIH P30 Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine
Director, Center for Animal Transgenesis
Member, Abramson Cancer Center
Targeting Bistable Stem Cell States in Response to APC Loss in FAP
FAP is a tumor predisposition syndrome where epithelial cells of the intestine lose function of the tumor suppressor protein APC, resulting in the formation hundreds to thousands of precancerous polyps, some of which invariably progress to colorectal cancer. For over a quarter century, the study of APC loss has focused on the oncogenic activity of a downstream transcription factor called Beta Catenin which promotes uncontrolled cell proliferation. However, clinical observations indicate that colorectal tumors driven by APC loss are larger and more aggressive than those driven by oncogenic Beta Catenin mutations. These observations lead to a hypothesis that APC inactivation results in additional oncogenic effects that we have yet to fully understand. Recent work from our group has identified a second parallel pathway to Beta Catenin oncogenic activity downstream of APC loss. Specifically, we identified a molecular mechanism resulting in the stabilization of an additional oncogenic transcription factor, YAP, which promotes a cell state similar to that seen in fetal intestinal development. Remarkably, while both Beta Catenin and YAP-driven cell states are induced upon APC loss, they are mutually exclusive at the level of individual cells. Further, these cell states are readily interchangeable over very short time periods (hours to days). These observations provide insight into why traditional therapies targeting the Beta Catenin pathway have not been highly efficacious. Our current work is focused on identifying therapeutic strategies to push APC-null cells into one state or the other, as well as concomitantly targeting both states in an effort to arrest tumor progression in FAP, and more broadly in colorectal cancers.
