Date of Graduation
12-2015
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Shao-Cong Sun, Ph.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Qingyun Liu, Ph.D.
Committee Member
Jagan Sastry, Ph.D.
Committee Member
Kimberly Schluns, Ph.D.
Abstract
Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal inflammation can be caused by deregulated signaling events in IECs or immune cells; and chronic inflammation is often associated with reduced production of immunosuppressive cytokines such as interleukin (IL)-10 and aberrant production of inflammatory cytokines. However, the signaling factors involved in the regulation of intestinal inflammation and tumorigenesis are still poorly defined. Given the complexity of the molecular and cellular components contributing to these pathogenic processes, animal models represent an important tool for CRC studies.
This dissertation focuses on the study of a serine/threonine kinase, TANK Binding Kinase 1 (TBK1). Although TBK1 is best known as a mediator of type I interferon induction in antiviral innate immunity, recent evidence suggests the involvement of TBK1 in several other biological processes including cancer development. Based on in vitro studies using cancer cell lines, TBK1 has been implicated as an oncogenic kinase that mediates survival of KRAS-dependent lung and other cancers. However, the oncogenic role of TBK1 is controversial, since this finding has been challenged by a more recent study. Moreover, the in vivo role of TBK1 in CRC development, particularly during the early phase of adenoma formation, has not been studied. This dissertation project took an in vivo approach that involves the generation and characterization of an innovative mouse model in which Tbk1 is conditionally ablated in IECs. The data from my dissertation reveals an unexpected finding that TBK1 has a tumor-suppressive function in the intestine. IEC-specific Tbk1 ablation promotes adenoma formation in mice carrying a mutation in the Apc gene, a tumor-suppressor gene commonly mutated in the early stages of colon cancer development. Interestingly, Tbk1 expression is important for the crosstalk of IECs with intraepithelial lymphocytes that maintain the expression of immunosuppressive cytokine IL-10. These studies present the first in vivo model demonstrating the function of TBK1 during the process of intestinal adenoma development and suggest a mechanism of TBK1 action. These data also present a novel approach in determining the in vivo function of TBK1 early in the tumorigenic process as compared to previous findings based on the xenograft model of late-staged cancers. In addition, because the use of TBK1 inhibitor has been suggested for possible treatment in cancers of other tissue types, my findings argue for the precaution in the selection of treatment modalities targeting TBK1 in these patients; it is possible that long-term use of TBK1 inhibitors may pose an increased risk for adenoma growth in the intestine.
Keywords
TBK1, TANK binding kinase 1, colon cancer, adenomatous polyposis coli, APC min/+ mouse model, intestinal adenoma growth, IL-10, colorectal cancer, intestinal epithelial cell, intraepithelial lymphocyte