Alfonso Bellacosa, MD, PhD

Alfonso Bellacosa, MD, PhD
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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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Professor

Adjunct Professor, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University

Adjunct Professor, College of Science and Technology, Temple University

Adjunct Associate Professor, Department of Biochemistry, Drexel University College of Medicine

Lab Overview

The goal of our research is to clarify how alterations in genomic and epigenomic stability of CpG sequences lead to altered development and cancer formation. Mutations are often the consequence of defective DNA repair; we are particularly interested in the mammalian DNA repair enzymes that protect the integrity of CpG sequences in DNA: MBD4 and TDG. This is important because mutations at CpG sites represent about one third of all point mutations in cancer. In addition, CpG sites are also important for regulation of gene activity by an epigenetic process called DNA methylation.  We discovered a role of TDG in active DNA demethylation (Cortellino et al. Cell, 2011), which is highly relevant in the context of the recently identified oxidized cytosine variants that have expanded the information content of the genome: TDG is the only enzyme that efficiently removes 5-formylcytosine and 5-carboxylcytosine produced by the TET dioxygenases.

We are also interested in innovative approaches of cancer prevention and therapy that are rationally based on the analysis of genetic and epigenetic alterations of cancer cells.

Finally, we are interested in the molecular basis of hereditary cancer syndromes.

  • Thymine DNA Glycosylase in Active DNA Demethylization

    Thymine DNA Glycosylase in Active DNA Demethylization

  • Demythalization pathways

    Demythalization pathways

  • Mutagenesis by deamination of 5-methylcytosine and cytosine at CpG sites

    Mutagenesis by deamination of 5-methylcytosine and cytosine at CpG sites

  • Lack of cilia in Ift122 knock-out embryos

    Lack of cilia in Ift122 knock-out embryos

  • Ingenuity Pathway Analysis

    Ingenuity Pathway Analysis

    Educational Background

    • PhD, Genetics, University of Paris, 2001-2004
    • Postgraduate School of Hematology, Catholic University Medical School, Rome, 1988-1992
    • MD, Catholic University Medical School, Rome, 1982-1988
    • University of Naples Second Medical School, 1981-1982

    Honors & Awards

    • PhD, avec la mention Très Honorable, 2004
    • "Sir Paul Girolami" Award for Innovative Research in Biology and Medicine, presented by Nobel Laureates Edmund Fischer and Rita Levi-Montalcini, 1993
    • Fellowship from the Italian Association for Cancer Research, 1992-1994
    • Postdoctoral Fellowship from the "Lawrence Greenwald Foundation for Research on Leukemia and Lymphoma," 1989-1991
    • MD, 110/110 Summa Cum Laude, 1988

    People

    Research Interests

    • Role of DNA Repair in the stability of the genome and epigenome
    • Regulation of DNA methylation and DNA demethylation in development and cancer
    • Targeted epigenetic therapy
    • Hereditary Cancer

    Selected Publications

    Mancuso P., Tricarico R., Bhattacharjee V., Cosentino L., Kadariya Y., Jelinek J., Nicolas E., Einarson M., Beeharry N., Devarajan K., Katz R.A., Dorjsuren D.G., Sun H., Simeonov A., Giordano A., Testa J.R., Davidson G., Davidson I., Larue L., Sobol R.W., Yen T.J., Bellacosa A., Thymine DNA glycosylase as a novel target for melanoma. Oncogene. 38(19): 3710-3728, 2019.PMC6563616 https://www.ncbi.nlm.nih.gov/pubmed/30674989.

    Sannai M., Doneddu V., Giri V., Seeholzer S., Nicolas E., Yip S.C., Bassi M.R., Mancuso P., Cortellino S., Cigliano A., Lurie R., Ding H., Chernoff J., Sobol R.W., Yen T.J., Bagella L., Bellacosa A. Modification of the base excision repair enzyme mbd4 by the small ubiquitin-like molecule sumo1. DNA Repair. 82: 102687, 2019.PMC6785017. https://www.ncbi.nlm.nih.gov/pubmed/31476572.

    Turchetti D., Zuntini R., Tricarico R., Bellacosa A., Brca2 in ovarian development and function. N Engl J Med. 380(11): 1086-1087, 2019. https://www.ncbi.nlm.nih.gov/pubmed/30865813.

    Xu J, Cortellino S, Tricarico R, Chang WC, Scher G, Devarajan K, Slifker M, Moore R, Bassi MR, Caretti E, Clapper M, Cooper H, Bellacosa A. Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression. Oncotarget, 8(52):89988-97, 2017. PMC5685726

    Tricarico, R., Cortellino, S., Riccio, A., Jagmohan-Changur, S., van der Klift, H., Wijnen, J., Turner, D., Ventura, A., Rovella, V., Percesepe, A., Lucci-Cordisco, E., Radice, P., Bertario, L., Pedroni, M., Ponz de Leon, M., Mancuso, P., Devarajan, K., Cai, K.Q., Klein-Szanto, A.J.P., Neri, G., Møller, P., Viel, A., Genuardi, M., Fodde, R. and Bellacosa, A. Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis. Oncotarget. 2015 Dec 15;6(40):42892-904. PubMed

    Bellacosa, A. and Drohat A.C. Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites. (Invited Review) DNA Repair, 32:33-42 (2015). PubMed

    Bellacosa, A. Developmental disease and cancer: biological and clinical overlaps. (Invited Review) Am J Med Genet A, 161:2788-96 (2013). PubMed

    Dalton, S.R. and Bellacosa, A. DNA Demethylation by TDG. Epigenomics 4: 459-467 (2012). PubMed

    Cortellino, S., Xu, J., Sannai, M.,  Moore, R.,  Caretti, E., Cigliano, A., Le Coz, M., Devarajan, K., Wessels, A., Soprano, D., Abramowitz, L. K., Bartolomei, M.S. Rambow, F., Bassi, M.R., Bruno, T., Fanciulli, M., Renner, C., Klein-Szanto, A.J., Matsumoto, Y., Kobi, D., Davidson, I., Alberti, C., Larue, L., Bellacosa, A.  Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146:67-79 (2011). PubMed

    Bellacosa, A., Godwin, A.K., Peri, S., Devarajan, K., Caretti, E., Vanderveer, L., Bove, B., Slater, C., Zhou, Y., Daly, M., Howard, S., Campbell, K., Nicolas, E., Yeung, A.T., Clapper, M.L., Crowell, J.A., Lynch, H.T., Ross, E., Kopelovich, L., Knudson, A.G. Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations. Cancer Prev. Res. 3: 48–61 (2010). PubMed

    Howard, J.H., Frolov, A., Tzeng, C-W.D., Stewart, A., Midzak, A., Majmundar, A., Godwin, A.K., Heslin, M.J., Bellacosa, A., and Arnoletti, J.P. Epigenetic Downregulation of the DNA Repair Gene MED1/MBD4 in Colorectal and Ovarian Cancer. Cancer Biol. Ther. 8: 1-7 (2009). PubMed

    Cortellino, S., Wang, C., Wang, B., Bassi, M.R., Caretti, E., Champeval, D., Calmont, A., Jarnik, M., Burch, J., Zaret, K., Larue, L., Bellacosa, A. Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4. Dev. Biol. 325: 225-237 (2009). PMC2645042. PubMed

    Caretti, E., Devarajan, K., Coudry, R., Ross, E., Clapper, M.L., Cooper, H.S. and Bellacosa, A. Comparison of RNA amplification methods and chip platforms for microarray analysis of samples processed by laser capture microdissection. J. Cell. Biochem. 103: 556-563 (2008). PubMed

    Julien, S., Puig, I., Caretti, E., Bonaventure, J., Nelles, L., van Roy, F., Dargemont, C., Garcia de Herreros, A., Bellacosa, A. and Larue, L. Activation of NF-kB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26: 7445-7456 (2007). PubMed

    Turner, D.P., Cortellino, S., Schup, J.E., Caretti, E., Loh, T., Kinsella, T.J., Bellacosa, A. The DNA N-glycosylase MED1 exhibits preference for halogenated pyrimidines and is involved in the cytotoxicity of 5-iododeoxyuridine. Cancer Res. 66: 7686-7693 (2006). PubMed

    Bellacosa, A., Kumar, C.C., Di Cristofano, A., Testa, J.R. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv. Cancer Res. 94: 29-86, 2005. PubMed

    Larue, L. and Bellacosa, A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 24: 7443-7454, 2005. PubMed

    Additional Publications

    This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
    Learn more about Research Volunteering.