655 W Baltimore Street
Education and Training
Dr. Passaniti received his Ph.D. from the University of Virginia, Biochemistry Department, at the School of Medicine. His work with Dr. Clive Bradbeer was on vitamin transport in bacteria. His post-doctoral work was at the University of Maryland, Baltimore County in the area of coated vesicles with Dr. Tom Roth and at the Johns Hopkins University in the area of tumor biology with Dr. Jerry Hart. While at Hopkins his work on the role of cell surface glycosylation in tumor metastasis led to a subsequent staff position at the NIH (National Institute on Aging) where he focused on tumor angiogenesis. He holds academic appointments at the University of Maryland in the Department of Pathology, the Department of Biochemistry & Molecular Biology, and the Program in Oncology at the Marlene and Stewart Greenebaum Comprehensive Cancer Center. In addition to his research programs in angiogenesis and breast cancer biology he also directs the Advanced Cancer Biology course in the Molecular Medicine program and participates in clinical conferences for medical students in Cell and Molecular Biology.
Breast cancer, angiogenesis, transcriptional regulation, cell signaling
D’Souza, DR, Salib, M, Bennett, J, Mochin-Peters, M, Asrani, K, Goldblum, SE, Renoud, KJ, and Passaniti, A (2009) Hyperglycemia regulates RUNX2 activation through the aldose reductase polyol pathway. J Biol Chem, 284: 17947-17955. PMID: 19383984
Zhang, Y., Ali, T.Z., Zhou, H., D’Souza, D.R., Lu, Y., Jaffe, J., Liu, Z., Passaniti, A., and Hamburger, A.W. (2010) ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer. Cancer Res. 70:240-8. PMID:20048076
D’Souza, DR, Girnun, G., Pierce, A., and Passaniti, A. (2010) Glucose metabolism, transcriptional regulation, and angiogenesis. Curr. Topics Biochem. Res. 11(2): 41-55.
Pierce, AD, Anglin, IE, Vitolo, MI, Mochin, MT, Underwood, KF, Goldblum, SE, Kommineni, S, and Passaniti, A. (2012) Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype. J. Cell. Biochem. 113(1):282-92 PMID: 21913213
Underwood, K.F., D’Souza, D.R., Pierce, A.D., Mochin, M.T., Kommineni, S., Bennett, J., Choe, M., Gnatt, A., Habtemariam, B., MacKerell, and Passaniti, A. (2012) Regulation of RUNX2 transcription factor-DNA interactions and cell proliferation by Vitamin D3 (cholecalciferol) prohormone activity. J. Bone Min. Res. 27(4):913-25, PMID:22189971
Mochin, M.T., Underwood, K.F., Pierce, A.D., Cooper, B., McLenithan, J.C., Nalvarte, C., MacKerell, A.D., Arbiser, J., Karlsson, A.I., Moise, R.A., A.D., Moskovitz, J., and Passaniti, A. (2015) A Role for Methionine Sulfoxide Reductase-A in Redox Regulation of RUNX2 DNA-binding Activity. Microvascular Res, 97:55–64 PMID: 25283348
Choe, M, Chumsri, S, Bhandary, Brusgard, JL, L, Zhao, XF, Lu, S, Goloubeva, OG, Polster, BM, Fiskum, GM, Girnun, GD, Kim, MS and Passaniti, A (2015) The RUNX2 transcription factor negatively regulates SIRT6 expression to alter glucose metabolism in breast cancer cells. J Cell Biochem.116(10):2210-26 PMID: 25808624
Brusgard, J.L., Choe, M., Chumsri, S., Renoud, K., MacKerell, A.D., Sudol, M., and Passaniti, A. (2015) RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells. Oncotarget,6(29):28132-50 PMID: 26320173
Brusgard, J.L. and Passaniti, A. (2013) RUNX2 transcriptional regulation in development and disease in “Nuclear Signaling Pathways and Targeting Transcription in Cancer”; Series Title: “Cancer Drug Discovery and Development”; edited by Rakesh Kumar; Springer, New York/Heidelberg.
Li, Z., Yang, Z., Passaniti, A., Lapidus, R., Liu, X., Cullen, K., and Dan, H.C. (2016) A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-κB regulates head and neck squamous cell carcinoma proliferation. Oncotarget Feb 17. doi:10.18632/oncotarget.7441; PMID: 26895469
Jeffrey Twum-Ampofo, Dexue Fu, Antonino Passaniti, Arif Hussain, and M. Minhaj Siddiqui (2016) Metabolic Targets for Potential Prostate Cancer Therapeutics. Curr Opinion in Oncology, 28(3):241-7. PMID: 26907571
Passaniti, A., Brusgard, J.L., Qiao, Y., Sudol, M., and Finch-Edmondson, M. (2017) Roles of RUNX in Hippo Pathway Signaling. Adv Exp Med Biol 962:435-448. PMID 28299672
My laboratory studies regulation of angiogenesis by the transcription factor RUNX2, which regulates EC interactions with the extracellular matrix and with other ECs (Sun et al. Cancer Res 61:4994-5001, 2001; Sun et al Oncogene 23:4722-34, 2004). Our hypothesis is that RUNX2 is expressed in the neovasculature and may regulate the expression of downstream genes involved in EC migration, proliferation, and survival including proteases (MT1MMP, MMP13, MMP9), angiogenic factors (VEGF), and matrix molecules (bone sialoprotein, osteopontin). A novel alternatively spliced RUNX2 variant that we identified (Sun et al Oncogene 23:4722-34, 2004) appears to modulate the expression of the p21(CIP1) gene, which is an important cyclin-dependent kinase inhibitor that controls cell-cycle progression and proliferation. We have recently found that RUNX2 activity is regulated by nutrient levels and glucose-mediated autocrine IGF-1 secretion and IGFR phosphorylation (D’Souza et al J Biol Chem, 284: 17947-17955, 2009). Inhibition of Runx2 activity in hyperglycemia is mediated by aldose reductase (AR) expression (sorbitol pathway) and production of reactive oxygen species. Further, we have developed a high-throughput DNA binding ELISA method to measure RUNX2 activity that could be used for the rapid screening of anti-angiogenic and anti-tumor compounds.
BREAST CANCER RESEARCH
RUNX2 promotes oncogenic transformation through its direct interaction with the coactivator protein, Yap, which is known to associate with proto-oncogenes of the c-src family (Vitolo et al. Cancer Biol Ther. 6:1-8, 2007). Therefore, we have now begun to investigate the mechanisms through which RUNX2 regulates breast cancer metastasis by looking at breast tumor cells expressing variable levels of RUNX2 both in culture models and in vivo. We are using state of the art transcriptional and cell cycle analysis methods, such as electrophoretic mobility shift assays (EMSA), DNA precipitation assays (DNAP), chromatin immunoprecipitation (ChIP), and FACS to measure DNA interactions with RUNX2 and its associated cofactors. Two recent developments have demonstrated the importance of metabolic regulation by RUNX2 in breast cancer cells (Choe et al. J Cell Biochem 116:2210-26,2015) and the cooperation of RUNX2 and Hippo signaling mediator, TAZ, in promoting BC mammosphere growth and survival (Brusgard et al. Oncotarget 6:28132-50, 2015).
The context-specific nature of many transcription factor dependencies is likely to lead to the identification of a large number of therapeutic opportunities. Basic research that investigates mechanisms of transcriptional regulation in normal and cancer contexts will be crucial to advance this important area of translational cancer research. There are many possible therapeutic targets in transcription factor signaling but demonstrating therapeutic efficacy has been a barrier to progress. We have taken a direct drug discovery approach using computer-aided drug design (CADD) to find novel compounds that interfere with RUNX2:DNA binding and transcriptional activity. This approach may overcome drug resistance and prevent or treat BC progression. We have identified novel small molecules that interact with the RUNX2:DNA binding pocket (Figure 2) and inhibit RUNX2 DNA binding, transcriptional activity, BC proliferation and mammosphere formation. One of these lead compounds is a potent inhibitor of RUNX2 DNA binding and transcriptional activity in live cells and animal models of breast cancer.