Assistant Professor of Medicine and
Adjunct Assistant Professor of Oncological Sciences
B.S. Westminster College, Salt Lake City
Ph.D. University of Utah
Melinda Angus-Hill's Lab Page
Melinda Angus-Hill's PubMed Literature Search
Molecular Biology Program
Metastasis, TCF/LEF, WNT/β-catenin, mouse models Adenomatous polyposis coli (APC) and colon cancer
The WNT/β-catenin signaling pathway plays a critical role during embryonic development and is often exploited by tumors to promote cell growth. The majority of familial and sporadic colorectal cancers harbor genetic mutations in APC (which lead to familial adenomatous polyposis, or FAP) a key component of the Wnt signaling pathway. Several mouse models have been developed to recapitulate APC mutations commonly associated with human colon cancers. Consistent with human FAP, mice carrying a specific mutation in the Apc gene (ApcMin/+) develop intestinal polyps. However, these animals, unlike humans, get few colon tumors. The TCF/LEF transcription factors (TCF1, LEF1, TCF3, and TCF7L2) are downstream transcription factors that are effectors of the WNT/β-catenin signaling pathway.
Metabolic syndrome is a cluster of abnormalities associated with increased risk of developing type 2 diabetes (T2D), cardiovascular disease, and cancer. The function of the TCF/LEF family member TCF7L2 may underlie the development of metabolic syndrome since multiple studies have shown it is involved in both T2D and colon cancer. TCF7L2 loss-of-function mutations have been identified in approximately 10% of primary colorectal cancers and have been shown to enhance cell growth in vitro. We developed a unique mouse model system that enabled us to firmly establish that loss of TCF7L2 leads to continued proliferation of colonic epithelial cells and significantly enhances colon tumorigenesis when combined with an initiating mutation in the Apc gene. In T2D, a number of studies have shown that certain human TCF7L2 variants are associated with increased risk of T2D. This raises the possibility that colon cancer and T2D, diseases that arise from apparently independent causes, may converge in a common pathway(s) characterized by effects resulting from deregulated TCF7L2 function.
While approximately one-third of the general population harbors deleterious TCF7L2 mutations, only a subset go on to develop colon cancer or T2D, suggesting the role of additional factors (environmental and/or genetic) that increase the risk of developing disease. My laboratory uses mouse genetics and molecular and biochemical approaches to pursue our research efforts. The central focus of my laboratory is to unravel the normal role(s) of TCF7L2, and at the same time increase our understanding of the etiology of TCF7L2-related mutations in colon cancer and metabolic disorders. Our long term goal is to develop a strategy to decrease the risk of Tcf7l2-dependent chronic disease risk at a population level.
- Bice BD, Stephens MR, Georges SJ, Venancio AR, Bermant PC, Warncke AV, Affolter KE, Hidalgo JR, Angus-Hill ML. Environmental Enrichment Induces Pericyte and IgA-Dependent Wound Repair and Lifespan Extension in a Colon Tumor Model. Cell Rep. 2017 Apr 25;19(4):760-773.
- Hammond E*, Lang J*, Maeda Y, Pleasure D, Angus-Hill M, Xu J, Horiuchi M, Deng W, Guo F. The Wnt effector transcription factor 7-like 2 positively regulates oligodendrocyte differentiation in a manner independent of Wnt/β-catenin signaling. J Neurosci. 2015 Mar 25;35(12):5007-22.
- Hong Y, Manoharan I, Suryawanshi A, Majumdar T, Angus-Hill ML, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Res. 2015 Feb 15;75(4):656-65.
- Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. J Immunol. 2014 Oct 15;193(8):4203-13.
- Angus-Hill M, Elbert KM, Hidalgo J, Capecchi MR. T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. Proc Natl Acad Sci USA. 2011 Mar 22;108(12):4914-9.
- Mathew SJ, Hansen JM, Merrell AJ, Murphy MM, Lawson JA, Hutcheson DA, Hansen MS, Angus-Hill M, Kardon G. Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development. 2011 Jan;138(2):371-84.
- Romeo MJ, Angus-Hill M, Sobering AK, Kamada Y, Cairns BR, Levin DE. HTL1 encodes a novel factor that interacts with the RSC chromatin remodeling complex in Saccharomyces cerevisiae. Mol Cell Biol. 2002 Dec;22(23):8165-74.
- Angus-Hill M, Schlichter A, Roberts D, Erdjument-Bromage H, Tempst P, Cairns BR. A Rsc3/Rsc30 zinc cluster dimer reveals novel roles for the chromatin remodeler RSC in gene expression and cell cycle control. Mol Cell. 2001 Apr;7(4):741-51.
- Angus-Hill M, Dutnall RN, Tafrov ST, Sternglanz R, Ramakrishnan V. Crystal structure of the histone acetyltransferase Hpa2: A tetrameric member of the Gcn5-related N-acetyltransferase superfamily. J Mol Biol. 1999 Dec 17;294(5):1311-25.
- White-Ziegler CA, Angus Hill M, Braaten BA, van der Woude MW, Low DA. Thermoregulation of Escherichia coli pap transcription: H-NS is a temperature-dependent DNA methylation blocking factor. Mol Microbiol. 1998 Jun;28(6):1121-37.
*contributed equally to this work