Colorectal cancer is a common malignancy that demands improved diagnosis and treatment. The long-term goal of my lab is to develop new treatments and preventive measures for colon cancer. To achieve this goal, we rely on the analyses of human tumor specimens to define alteration in critical pathways that are disrupted during colon tumor formation. We focus on the idea that colon tumor cells are confused about their identity and are interested in finding ways to restore their “normal thinking.” Their confusion comes, in part, from the incorrect storage and access of the cellular computer system…DNA. Our work studies how the instructions provided by DNA are accessed and why this goes wrong in tumors. We work closely with clinical colleagues to test new ideas for therapies that can reprogram or rehabilitate cancer cells.
Colorectal cancer is a common malignancy in terms of new cases and deaths among men and women in the United States. The past fifty years have seen only marginal improvement in survival from this disease. This improvement is largely due to improved early diagnosis and surgical treatment. The importance of early diagnosis is reflected by the inverse relationship between survival and stage of diagnosis. Patients can expect a greater than 90% survival rate when the cancers are confined to the colon or rectum. This survival rate drops to 66% if the cancer has spread to surrounding tissues and to 8.5% if the primary carcinoma has metastasized. The majority of carcinomas, 57%, are diagnosed at the second and third stages where survival rates are dramatically reduced. As such, the problem of colon cancer remains an important, unmet medical need that demands a better understanding of the disease as well as improved diagnosis and treatment. Our long-term goal is to facilitate the development of new preventive measures for colon adenoma and carcinoma formation by understanding the earliest cellular perturbations leading to disease development.
APC and Retinoic Acid Biosynthesis in Cancer and Development - One type of inherited colon cancer predisposition, familial adenomatous polyposis (FAP), results from mutations in a single gene known as adenomatous polyposis coli (APC). Recent studies from our laboratory indicate that APC may promote colonocyte differentiation by stimulating the production of retinoic acid. Retinoic acid is a lipid mediator with important roles in controlling cell patterning, fate, and differentiation. Central to the ability of a cell to respond to retinoic acid is the requirement of first converting dietary retinol (vitamin A) into retinoic acid, a process that occurs via two enzymatic steps. The first step of this process converts retinol into retinal and is mediated by alcohol dehydrogenases (ADH) and short chain dehydrogenases (SDR). The second step involves conversion of retinal into retinoic acid via aldehyde dehydrogenases (ALDH). Given the required conversion of vitamin A, retinoic acid production is limited to cells harboring the necessary biosynthetic enzymes. We have demonstrated that loss of retinoic acid production is an early event following mutation of APC and that this contributes to the mis-fating of intestinal epithelial cells.
DNA Methylation in Cancer and Development - Much of our understanding of gene dysfunction in disease comes from the concept of gene mutation or gene deletion. Epigenetic mechanisms, however, can also lead to a functional “knockout” of key disease genes. Among these epigenetic mechanisms is silencing of genes by DNA methylation. DNA methylation in mammalian cells occurs at cytosines residing within CpG dinucleotides. Alterations in developmentally established methylation patterns may alter the gene expression patterns within tissues and cause or promote disease. We are currently studying how methylation patterns are established and the potential for targeting enzymes that establish and interpret methylation patterns with therapeutics.
Zebrafish as a Model for Studying Intestinal Development and Differentiation - Zebrafish have emerged as a powerful genetic model system for identifying and mapping signaling pathways critical to embryological development. Since the zebrafish gastrointestinal tract displays many features similar to that of higher vertebrates, we utilize zebrafish as a model system to study the role of APC, retinoic acid, and DNA methylation in directing development and differentiation of the gastrointestinal tract. For example, using this system we have recently confirmed a genetic relationship between APC and retinoic acid in controlling zebrafish gut development and differentiation. Our data show that knock down of either APC or retinoic acid biosynthesis in zebrafish results in the development of intestines that lack differentiated epithelial cells. Treatment of either APC mutant embryos with retinoic acid rescued the defective phenotypes, thus placing retinoic acid downstream of the APC tumor suppressor.
B.S., University of Michigan, Ann Arbor, MI, 1987
Ph.D., University of Colorado, Denver, CO, 1991
Postdoc, University of Utah, Salt Lake City, Utah 1991-93
2011 - present: Chair, American Cancer Society Review Committee, TBE
2011 - present: Full Member NIH Scientific Review Committee, MONC
2010 - present: Administrative Oversight, Translational Oncology Core
2009 - present: Administrative Oversight, Comparative Oncology Core
2009 - present: Administrative Oversight, Tissue Research and Application Core
2009 - present: Administrative Oversight, Drug Screening Resource
2007 - present: Senior Director of Early Translational Research, HCI
2003 - present: CCSG Gastrointestinal Cancers Program Leader, University of Utah
2007 - 2009: Chair, University of Utah Drug Screening Resource
2007 - 2011: American Cancer Society Review Committee, TBE
2007- 2011: Ad Hoc NIH Scientific Review Committee, MONC
2007 - 2009: Chair, Tissue Resource and Application Core
2006: Reviewer and Ad Hoc member NCI/IRG Subcommittee A
2006 - 2008: Chair, Translational Research Development Partnership, HCI
2005 - 2007: Director’s Translational Research Initiative Planning Committee
2005: Reviewer and Ad Hoc member NCI/IRG Subcommittee A
1997 - 2005: Co-director, Huntsman Cancer Institute Microarray Facility
2003 - 2005: Chair, Department of Oncological Sciences Faculty Search Committee
2003 - 2005: Chair, Department of Oncologcial Sciences Curriculum Committee
2003 - 2005: Chair, Biological Chemistry Program Admissions Committee
1995 - 1996: Genomics and Bioinformatics Program Team Leader, Pharmacia, Inc.
American Association for Pharmacology and Experimental Therapeutics
American Association for Cancer Research
American Society of Biological Chemists and Molecular Biologists
American Association for the Advancement of Science
Joined OMRF Scientific Staff in 2013
Sandoval IT, Delacruz RG, Miller BN, Hill S, Olson KA, Gabriel AE, Boyd K, Satterfield C, Remmen HV, Rutter J, Jones DA. A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC). Elife. 2017 Apr 11;6. pii: e22706. PMCID: PMC5388534
Borras E, San Lucas FA, Chang K, Zhou R, Masand G, Fowler J, Mork ME, You YN, Taggart MW, McAllister F, Jones DA, Davies GE, Edelmann W, Ehli EA, Lynch PM, Hawk ET, Capella G, Scheet P, Vilar E. Genomic Landscape of Colorectal Mucosa and Adenomas. Cancer Prev Res (Phila). 2016 May 24. [Epub ahead of print] [Abstract] PMCID:PMC4941624
Sandoval IT, Manos EJ, Van Wagoner RM, Delacruz RG, Edes K, Winge DR, Ireland CM, Jones DA. Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F. Chem Biol. 2013 20: 753-63. PMCID:PMC3715381
Garrido-Laguna I, McGregor KA, Wade M, Weis J, Gilcrease W, Burr L, Soldi R, Jakubowski L, Davidson C, Morrell G, Olpin JD, Boucher K, Jones D, Sharma S. A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer. Invest New Drugs. 2013 Oct;31(5):1257-64. PMID: 23504398
Ridges S, Heaton WL, Joshi D, Choi H, Eiring A, Batchelor L, Choudhry P, Manos EJ, Sofla H, Sanati A, Welborn S, Agarwal A, Spangrude GJ, Miles RR, Cox JE, Frazer JK, Deininger M, Balan K, Sigman M, Müschen M, Perova T, Johnson R, Montpellier B, Guidos CJ, Jones DA, Trede NS. Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood. 2012 Jun 14;119(24):5621-31. PMCID:PMC3382926
Wu SF, Zhang H, Hammoud SS, Potok M, Nix DA, Jones DA, Cairns BR. DNA methylation profiling in zebrafish. Methods Cell Biol. 2011;104:327-39. PMID:21924171
Wei X, Bugni TS, Harper MK, Sandoval IT, Manos EJ, Swift J, Van Wagoner RM, Jones DA, Ireland CM. Evaluation of pyridoacridine alkaloids in a zebrafish phenotypic assay. Mar Drugs 8: 1769-1778, 2010. PMCID:PMC2901824
Rai K, Sarkar S, Broadbent TJ, Voas M, Grossmann KF, Nadauld LD, Dehghanizadeh S, Hagos FT, Li Y, Toth RK, Chidester S, Bahr TM, Johnson WE, Sklow B, Burt R, Cairns BR, Jones DA. DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. Cell 142: 930-942, 2010. PMCID:PMC2943938
Rai K, Jafri IF, Chidester S, James SR, Karpf AR, Cairns BR, Jones DA. Dnmt3 and G9a cooperate for tissue-specific development in zebrafish. J Biol Chem. 2010 Feb5;285(6):4110-21. PMCID:PMC2823551