John Digiovanni, Ph.D.
Professor and Coulter R. Sublett Chair
Division of Pharmacology & Toxicology
College of Pharmacy, The University of Texas at Austin
Research in my laboratory has focused for many years on understanding how cancer develops and on the identification of novel targets, mechanisms and strategies for cancer prevention. Cancer is a disease involving gene-environment interactions and therefore understanding both environmental influences as well as genetic factors is key to developing the most effective strategies for preventing cancer. In addition, understanding the early cellular, biochemical and molecular changes that transform normal cells into cancer cells is essential if we are to eventually eradicate cancer as a major human disease.
There are several major research projects that are currently ongoing in my laboratory. First, one major research area focuses on identifying specific cellular signaling pathways that are disrupted during tumor development and progression. Signaling pathways currently under study include the PI3K/Akt/mTOR pathway and Signal Transducers and Activators of Transcription (Stats), especially Stats1,3 and 5. Another important research area involves studies aimed at identifying the target cells (i.e., stem/progenitor cells) for tumor development. Using a novel gene knockout strategy we have recently shown that keratinocyte stem cells located in the bulge region of hair follicles are the major targets for the initiation of skin (epithelial) tumors in mice. Further study of these cells and their role in tumor development will lead to novel strategies and targets for both prevention and treatment of epithelial cancers. Another important area of research involves identifying genes that confer susceptibility to environmentally-induced cancer. These studies have used genetic crosses between sensitive and resistant mice to map genes involved in the promotion of skin tumors in mice. Using this approach we recently mapped and identified a gene (Gsta4) on Chr 9 that is involved in susceptibility to skin tumor development in mice. We also found that polymorphisms in this gene are risk alleles for human non-melanoma skin cancer (both basal cell carcinoma and squamous cell carcinoma). We are currently examining this gene in other human cancers and also working to identify genes in other regions of mouse chromosomes identified from our initial screen that harbor susceptibility loci. These studies also incorporate the novel approach of using “genetical genomics” to help identify novel genes, pathways and networks involved in cancer susceptibility.
A major new research direction in my laboratory focuses on the impact of obesity on cancer development and progression, including obesity that occurs early in life. In fact, obesity in children has risen dramatically in recent years. Obesity in both adults and children increases risk of cancer development for a number of important cancers. However, the mechanism(s) that underlie the effects of obesity on cancer development and progression are not well understood. We are currently studying the impact of obesity on cellular signaling pathways in several tissues in relation to its effects on cancer development. Recent studies have revealed that obesity alters growth factor signaling in multiple epithelial tissues through modulation of cross-talk between the IGF-1 and EGF-receptors. The overall goal of this research is to identify molecular targets and strategies to offset the increased cancer risk and mortality associated with obesity.
Cancers currently under study in the laboratory include skin cancer (both melanoma and non-melanoma skin cancers), prostate cancer, head and neck squamous cell carcinoma and lymphoma.
Meadows, G.G., DiGiovanni, J., Minor, L., and Elmer, G.W. Some biological properties and an in vivo evaluation of tryosine phenol-lyase on growth of B-16 melanoma. Cancer Res., 36:167-171, 1976.
DiGiovanni, J., Slaga, T.J., Berry, D.L., and Juchau, M.R. Metabolism of 7,12-dimethylbenz[a]anthracene in mouse skin homogenates analyzed with high-pressure liquid chromatography. Drug Metab. Dispos., 5:295-301, 1977.
Slaga, T.J., Thompson, S., Berry, D.L., DiGiovanni, J., Juchau, M.R., and Viaje, A. The effects of benzoflavones on polycyclic hydrocarbon metabolism and skin tumor initiation. Chem. Biol. Interactions, 17:297-312, 1977.
Berry, D.L., Slaga, T.J., Viaje, A., Wilson, N.M., DiGiovanni, J., Juchau, M.R., and Selkirk, J.K. Effect of trichloropropene oxide on the ability of polyaromatic hydro-carbons and their k-region oxides to initiate skin tumors in mice and to bind to DNA in vitro. J. Natl. Cancer Inst., 58:1051-1055, 1977.
DiGiovanni, J., Viaje, A., Berry, D.L., Slaga, T.J., and Juchau, M.R. Tumor-initiating ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254 in the two-stage system of mouse skin carcinogenesis. Bull. Environ. Contam. Toxicol., 18:552-557, 1977.
DiGiovanni, J., Slaga, T.J., Viaje, A., Berry, D.L., Harvey, R.G., and Juchau, M.R. Effects of 7,8-benzoflavone on skin tumor-initiating activities of various 7-and 12-substituted derivatives of 7,12-dimethylbenz[a]anthracene in mice. J. Natl. Cancer Inst., 61:135-140, 1978.
Juchau, M.R., Namkung, M.J., Jones, A.H., and DiGiovanni, J. Biotransformation and bioactivation of 7,12-dimethylbenz[a]anthracene in human fetal and placental tissues. Analyses of HPLC profiles and studies with Salmonella typhimurium. Drug Metab. Dispos., 6:273-281, 1978.
Berry, D.L., DiGiovanni, J., Juchau, M.R., Bracken, W.M., Gleason, G.L., and Slaga, T.J. Lack of tumor-promoting ability of certain environmental chemicals in a two-stage mouse skin tumorigenesis assay. Res. Commun. Chem. Pathol. Pharmacol., 20:101-108, 1978.
DiGiovanni, J., Berry, D.L., Juchau, M.R., and Slaga, T.J. 2,3,7,8-tetrachlorodi-benzo-p-dioxin: Potent anticarcinogenic activity in CD-1 mice. Biochem. Biophys. Res. Commun., 86:577-584, 1979.
Juchau, M.R., DiGiovanni, J., Namkung, M.J., and Jones, A.H. A comparison of the capacity of fetal and adult liver, lung, and brain to convert polycyclic aromatic hydrocarbons to mutagenic and cytotoxic metabolites in mice and rats. Toxicol. Appl. Pharmacol., 49:171-178, 1979.
Slaga, T.J., Huberman, E., DiGiovanni, J., Gleason, G.L., and Harvey, R.G. The importance of the bay region diol-epoxide in 7,12-dimethylbenz[a]anthracene skin tumor initiation and mutagenesis. Cancer Lett., 6:213-220, 1979.