DEPARTMENT: Basic Sciences Research CAMPUS AFFILIATION: North OFFICE: Geisinger Commonwealth School of MedicineMedical Sciences Building 525 Pine St., Office 3044 Scranton, PA 18509 PHONE: 570-504-9646 FAX: 570-504-9636 EMAIL: email@example.com EDUCATION: Bachelor – SUNY-Binghamton, Binghamton, NY Master – Fordham University, Bronx, NY PhD – Fordham University, Bronx, NY Postdoctoral – Montefiore Medical Center, Bronx, NY BIO: Michael Bordonaro, PhD is associate professor of molecular biology in the Department of Basic Sciences. Dr. Bordonaro holds a PhD in the biological sciences from Fordham University, Bronx, New York. Additionally, Dr. Bordonaro completed a postdoctoral fellowship in the Department of Oncology at the Montefiore Medical Center, Bronx, New York, where he received an American Institute for Cancer Research Postdoctoral Award for his work on the effects of dietary components on the development of colorectal cancer. Dr. Bordonaro later held the position of associate research scientist at the Yale University School of Medicine and has also served as a research coordinator for Keren Pharmaceutical. His research interests are in molecular oncology, particularly the Wnt signaling pathway in colorectal cancer, as well as in gene therapy for colorectal cancer, and quantum biology including adaptive mutation. RESEARCH INTERESTS: Colorectal cancer, gene therapy, adaptive mutation in cancer, Wnt signaling in colorectal cancer and human aging RESEARCH DESCRIPTION: Deregulation of Wnt signaling is responsible for the initiation of most cases of colorectal cancer, through the abnormal, constitutive activation of genes related to cellular proliferation. However, we have observed that hyper-activation of Wnt activity in colorectal cancer (CRC) cells by histone deacetylase inhibitors (HDACis) induces CRC cell apoptosis, rather than proliferation. Thus, we believe that Wnt signaling exists as a continuum, in which moderate levels of Wnt activity stimulates colonic cell proliferation, but very low or very high levels of Wnt activity promote apoptosis, likely through differential expression of direct and indirect Wnt target genes. HDACis include agents currently in clinical trial, and also include butyrate, a breakdown product of dietary fiber; the action of butyrate in stimulating Wnt activity and apoptosis may in part explain the protective activity of fiber against CRC. Determination of how butyrate may inhibit the initiation and progression of colorectal neoplasms can assist in the development of (a) superior dietary regimens for CRC prevention and (b) new chemopreventive strategies based upon hyper-activation of Wnt signaling. Further, dissection of the mechanisms whereby HDACis induce Wnt signaling and apoptosis in CRC cells may lead to more effective therapeutic use of these agents against established CRC. Given the generally poor prognosis of advanced/metastatic CRC, additional therapeutic options are required. Gene therapy approaches are promising, but are limited by potential problems with viral delivery systems. We have developed a modular Wnt-targeted Cre-Lox-mediated gene therapy system which has demonstrated preliminary therapeutic promise in cell lines derived from both primary CRC as well as a lymph node metastasis. Further analysis of this system is required, and we plan to compare its efficacy with other Wnt-targeted gene therapy approaches. Importantly, we also plan to combine our gene therapy system with a novel non-viral delivery method, which exhibits low toxicity in cell culture experiments. This may eventually lead to new therapeutic options for individuals with advanced/metastatic Wnt-positive CRC. Adaptive mutation has been observed in single cell organisms; we have an interest in investigating adaptive mutation in mammalian cells and in carcinogenesis and resistance to cancer therapeutics. Specifically, we wish to evaluate a model in which quantum mechanical effects underlie adaptive mutation, including the development of cancer. Our research has been supported by grants from National Cancer Institute and American Institute for Cancer Research. Read more details of the grant online. STUDENT RESEARCH OPPORTUNITIES: The primary focus of Dr. Michael Bordonaro’s research is to understand how modulation of the Wnt signaling pathway influences decisions of cell growth vs. cell death in colorectal cancer (CRC) so that more effective preventive and/or therapeutic approaches against this disease may be developed. Wnt signaling is normally important for cell growth and differentiation. However, mutations in this cellular pathway that result in deregulated Wnt activity cause abnormal colonic cell growth that eventually leads to cancer. Although moderate Wnt signaling activity induces cell growth, extremely high levels of Wnt signaling can cause cell death. Butyrate, a product of dietary fiber, increases Wnt signaling to an extent that promotes CRC cell death; this may in part explain the protective role of fiber against CRC. Therefore, we are interested in studying: (a) the changes in Wnt-specific gene expression caused by butyrate that results in cell death, (b) the mechanisms by which CRC cells can become resistant to butyrate and how this resistance can be overcome, (c) how various transcriptional factors and other cell signaling pathways interact with Wnt signaling to mediate the effects of butyrate and (d) how aberrant Wnt signaling can be targeted for gene therapy approaches against CRC. PUBLICATIONS: Lazarova, D., Bordonaro, M. Hypothesis: ZEB1 mediates drug resistance and EMT in p300-deficient CRC. J Cancer 8: 1453-1459 (2017). Bordonaro, M., Shirasawa, S, and Lazarova, D.L. In hyperthermia increased ERK and WNT signaling suppress colorectal cancer cell growth. Cancers 8:49 (2016). Cho, Y., Gutierrez, L., Bordonaro, M., Russo, D., Anzelmi, F., Hooven, J.T., Cerra, C., and Lazarova. D.L. Effects of propolis and gamma-cyclodextrin on intestinal neoplasia in normal weight and obese mice. Cancer Medicine 5: 2448-2458 (2016). Lazarova, D.L., and Bordonaro, M. Vimentin, colon cancer progression and resistance to butyrate and other HDACis. J. Cell. Mol. Med. 20: 989-993 (2016). Bordonaro, M., and Lazarova, D.L. Determination of the role of CBP and p300 mediated Wnt signaling on colonic cells. JMIR Res. Protoc. 5: e66 (2016). Bordonaro, M., and Lazarova, D.L. Obesity is associated with a lower mutation threshold in colon cancer. J. Cancer 6: 825-831 (2015). Bordonaro, M., and Lazarova, D.L. CBP, p300, butyrate, and Wnt signaling in colorectal cancer. World J. Gastroenterology 21: 8238-8248 (2015). Bordonaro, M., Drago, E., Atamna, W., and Lazarova, D.L. Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy. PLoS One 9: e115068 (2014). Bordonaro, M., Chiaro, C.R., and May T. Experimental design to evaluate directed adaptive mutation in mammalian cells. JMIR Res. Protoc. 3:e74 (2014). Bordonaro, M., and Lazarova, D.L. Hypothesis: cell signaling influences age-related risk of colorectal cancer. J. Cell. Mol. Med. 19: 74-81 (2014). Lazarova, D.L., Chiaro, C., and Bordonaro, M. Butyrate induced changes in Wnt-signaling specific gene expression in colorectal cancer cells. BMC Research Notes 7: 226 (2014). Bordonaro, M., and Lazarova, D.L. Butyrate, WNT signaling, and colorectal cancer. In: Butyrate: Food sources, functions and health benefits. Nova Science Publishers, Inc. (Hauppauge, NY) (2014). Zeng, H., Lazarova, D.L., and Bordonaro, M. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World J. Gastrointestinal Oncol. 6 (2): 1-10 (2014). Lazarova, D.L., Lee, A., Wong, T., Marian, B., Chiaro, C., Rainey, C., and Bordonaro, M. Modulation of Wnt Activity and cell physiology by butyrate in LT97 microadenoma cells. J. Cancer 5: 203-213 (2014). Bordonaro, M., Venema, K., Putri, A.K., and Lazarova, D.L. Approaches that ascertain the role of dietary compounds in colonic cancer cells. World J. Gastrointestinal Oncol. 6 (1): 1-10 (2014). Drago, E., Bordonaro, M., Lee, S., Atamna, W., and Lazarova, D.L. Propolis augments apoptosis induced by butyrate via targeting cell survival pathways. PLoS One 8:e73151 (2013). Lazarova, D.L., Wong, T., Chiaro, C., Drago, E., and Bordonaro, M. p300 influences butyrate-mediated WNT hyperactivation in colorectal cancer cells. J. Cancer 4: 491-501 (2013). Lazarova, D.L., Chiaro, C., Wong, T., Drago, E., Rainey, A., O’Malley, S., and Bordonaro, M. CBP activity mediates effects of the histone deacetylase inhibitor butyrate on WNT activity and apoptosis in colon cancer cells. J. Cancer 4: 481-490 (2013). Bordonaro, M., and Ogryzko, V. Quantum biology at the cellular level-elements of the research program. BioSystems 112:11-30 (2013). Bordonaro, M. Minireview: Crosstalk between Wnt signaling and RNA processing in colorectal cancer. J. Cancer 4: 96-103 (2013). Chiaro, C., Lazarova, D.L., and Bordonaro, M. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells. Biochem. Biophys. Res. Commun. 428: 121-126 (2012). Lazarova, D.L., and Bordonaro, M. Extreme fluctuations in Wnt/beta-catenin signaling as an approach for colon cancer prevention and therapy. Advanced Studies in Biology 4: 351-362 (2012). Bordonaro, M., Tewari, S., Cicco, C.E., Atamna, W., and Lazarova, D.L. A switch from canonical to noncanonical Wnt signaling mediates drug resistance in colon cancer cells. PLoS One 6:e27308 (2011). Bordonaro, M., Tewari, S., Atamna, W., and Lazarova, D.L. The notch ligand Delta-like 1 integrates inputs from TGFBeta/Activin and Wnt pathways. Exp. Cell Res. 317: 1368-1381 (2011). Bordonaro, M. Modular Cre/lox system and genetic therapeutics for colorectal cancer. J. Biomed. Biotechnol. 2009:358230 (2009). Bordonaro, M. Chapter 19 role of wnt signaling in the development of type 2 diabetes. Vitam. Horm. 80: 563-581 (2009). Bordonaro, M., Lazarova, D.L., and Sartorelli, A.C. Role of Tcf-DNA binding and the chromatin remodeling factor Brg-1 in the modulation of Wnt activity by butyrate. Cell Cycle 7: 3472-3473 (2008). Bordonaro, M., and Sartorelli, A.C. Fiber, cancer stem cells, and the Wnt signaling continuum: possibilities for colorectal cancer prevention and therapeutics. Chinese J. Cancer (Ai Zheng), 27: 766-770 (2008). Bordonaro, M., Lazarova, D.L., and Sartorelli, A.C. Butyrate and Wnt signaling: a possible solution to the puzzle of dietary fiber and colon cancer risk? Cell Cycle 7:9:1178-1183 (2008). Bordonaro, M., Lazarova, D.L., and Sartorelli, A.C. Hyper-induction of Wnt activity: a new paradigm for the treatment of colorectal cancer? Oncol. Res. 17: 1-9 (2008). Bordonaro, M.*, Lazarova, D.L.*, and Sartorelli, A.C. The activation of beta-catenin by Wnt signaling mediates the effects of histone deacetylase inhibitors. Exp. Cell Res. 313: 1652-1666 (2007). Bordonaro, M., Lazarova, D.L., Carbone, R., and Sartorelli, A.C. Modulation of Wnt-specific colon cancer cell kill by butyrate and lithium. Oncol. Res. 14: 427-438 (2004). Bordonaro, M., Lazarova, D. L., and Sartorelli, A. C. Pharmacological and genetic modulation of Wnt-targeted cre lox-mediated gene expression in colorectal cancer cells. Nucleic Acids Res. 32: 2660-2674 (2004). Lazarova, D. L., Bordonaro, M., Carbone, R., and Sartorelli, A.C. Linear relationship between Wnt activity levels and apoptosis in colorectal carcinoma cells exposed to butyrate. Int. J. Cancer 110: 523-531 (2004). Bordonaro, M., Lazarova, D.L., Augenlicht, L.H., and Sartorelli, A.C. Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. Int. J. Cancer 97: 42-51 (2002). Lazarova, D.L., Bordonaro, M., and Sartorelli. A.C. Transcriptional regulation of the vitamin D(3) receptor gene by ZEB. Cell Growth Differ. 12: 319-326 (2001). Mariadason, J.M., Bordonaro, M., Aslam, F., Shi, L., Kuraguchi, M., Velcich, A., and Augenlicht, L.H. Downregulation of the beta-catenin-Tcf pathway is linked to colonic epithelial cell cycle arrest and differentiation. Cancer Res. 61: 3465-3471 (2001). Bordonaro, M., Mariadason, J.M., Aslam, F., Heerdt, B.G., and Augenlicht, L.H. Butyrate induced apoptotic cascade in colonic carcinoma cells: modulation of the beta-catenin-Tcf pathway, and concordance with effects of sulindac and trichostatin A, but not curcumin. Cell Growth Differ. 10: 713-720 (1999). Augenlicht, L.H., Bordonaro, M., Heerdt, B.G., Mariadason, J., and Velcich, A. Cellular mechanisms of risk and transformation. Ann. NY Acad. Sci. 889: 20-31 (1999). Augenlicht, L., Velcich, A., Mariadason, J., Bordonaro, M., and Heerdt, B. Colonic cell proliferation, differentiation, and apoptosis. Adv. Exp. Med. Biol. 470: 15-22 (1999). Bordonaro, M., and Augenlicht, L.H. The 3′ untranslated region of the carcinoembryonic antigen gene plays a minimal role in the regulation of gene expression. Cell Growth Differ. 8: 353-360 (1997). Bordonaro, M., Saccomanno, C.F., and Nordstrom, J.L. An improved T1/A ribonuclease protection assay. Biotechniques 16: 428-430 (1994). Bordonaro, M. and Nordstrom, J.L. Different mechanisms are responsible for the low accumulation of transcripts from intronless and 3′ splice site deleted genes. Biochem. Biophys. Res. Comm. 203: 128-132 (1994). Saccomanno, C.F., Bordonaro, M., Chen, J.S., and Nordstrom, J.L. A faster ribonuclease protection assay. Biotechniques 13: 846-850 (1992).