个人简介
I graduated from Washington College in Chestertown, MD with a B.S. degree in Biology. This was followed by postgraduate studies on the biochemistry and endocrinology of vitamin D at the University of Maryland at College Park, where I obtained the Ph.D. degree. My postdoctoral training was conducted at Case Western Reserve University in Cleveland, Ohio, where I worked on the molecular biology of glycoprotein hormones under the mentorship of Dr. John Nilson.
My first independent faculty position as an assistant professor was in the Department of Medicine at Case Western Reserve University, where I investigated the transcriptional control of the platelet-derived growth factor genes in glioblastoma and other human cancers. I moved my laboratory in 1993 to the Department of Pharmacology at the University of Kentucky in Lexington, where I continued my work on molecular mechanisms underlying cancer progression and metastasis. I have recently moved to the University of Maryland (June 2012) to continue this work, which has evolved to a focus on genes regulating the metastatic process in melanoma.
My work has been funded almost continously since 1993 by the NIH through NIDDK, NHLBI and the NCI. The laboratory is currently funded by a recent R01 grant focused on identification of metastasis-driving mutations in our new transgenic mouse model for metastatic melanoma. We are also developing other promising avenues in drug development that we hope will lead to new treatment prospects for advanced forms of melanoma.
I am a member of the Molecular and Structural Biology Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program in Oncology. As such, I collaborate with both clinical and basic research investigators to elucidate molecular mechanisms underlying metastasis in melanoma and other cancers, with the ultimate goal of identifying novel therapeutic targets and molecular markers for management of cancer patients with advanced disease
研究领域
Progression of cancer to lethal forms requires the acquisition of driver mutations and aberrant programs of gene expression that endow cells with the ability to grow at distant sites, a process known as metastasis. Current cancer therapies often fail as they are almost exclusively directed to the hyperproliferative phenotype of primary tumor cells, and do not effectively target the metastatic process. Clearly, there is a dire need for new treatment options to target cancer in its advanced forms. The primary thrust of my National Cancer Institute-funded research program has been the elucidation of molecular mechanisms that mediate cancer progression and metastasis, and has centered to a large extent on the NM23 family of metastasis suppressor genes. Our studies of the NM23-H1 isoform has yielded considerable insights into molecular mechanisms that suppress metastatic potential, with one of the most significant being our identification of a novel mechanism underlying metastasis-driving mutations in melanoma.
The NM23 Family of Metastasis Suppressor Genes
Metastasis suppressors inhibit the metastatic activity of cancer cells with little effect on primary tumor growth (Smith and Theodorescu, 2009). The mouse gene nm23-m1 was the first metastasis suppressor gene to be described, with confirmation of suppressor activity of its human homolog nm23-h1 in cell lines and in melanoma, breast carcinoma and other cancers (Hartsough and Steeg, 2000). Although mechanisms underlying metastasis suppressor activity of the NM23-H1/M1 protein are not well understood, it harbors three distinct enzymatic activities that might mediate its antimetastatic functions. First to be described was its nucleoside diphosphate kinase (NDPK) activity, which maintains balance in nucleotide pools by catalyzing transfer of -phosphate between NDPs and NTPs (Agarwal et al., 1978). NM23-H1 also possesses a histidine kinase activity that may mediate an anti-motility function of the molecule (Wagner et al., 1997).
Our laboratory was the first to describe an association of 3’-5’ exonuclease activity with the NM23-H1 protein (Ma et al., 2004), and we subsequently showed this activity to be essential for its metastasis suppressor function (Zhang et al., 2011). 3’-5’ exonucleases provide proofreading during DNA replication and repair (Shevelev and Hübscher, 2002), and consistent with this function, we showed the NM23 homolog in S. cerevisiae possesses antimutator activity (Yang et al., 2009). More recently, we have also demonstrated antimutator activity of NM23-H1 in UVR-treated melanoma cell lines, and that NM23-H1 specifically promotes both the nucleotide excision/NER (Jarrett et al., 2011) and double-strand break/DSBR (unpublished observations) pathways for DNA repair. Importantly, NM23 deficiency is associated with increased rates of spontaneous mutations in a variety of melanoma and nontransformed cell lines, strongly suggesting its expression may be essential for suppression of progression- and metastasis-driving mutations. Importantly, we have recently demonstrated a direct physical association of NM23-H1 with sites of DNA damage, strongly suggesting its direct participation in the DNA repair process. Using a transgenic mouse strain harboring a concurrent deficiency in both the nm23-m1 or nm23-m2 genes, we observe vulnerability to ultraviolet light-induced melanoma in situ, consistent with a DNA repair function in vivo (Jarrett et al., 2011). Moreover, this nm23-deficient genotype confers aggressive metastasis when bred into a mouse model of melanoma with otherwise low metastatic potential (Jarrett et al., submitted for publication). Taken together, our work has revealed an unexpected and significant mechanistic role for NM23 proteins in both initiation and progression of melanoma.
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Zhang, Q., McCorkle, J.R., Yang, M., Novak, M., and Kaetzel, D.M. (2011) Metastasis suppressor function of NM23-H1 requires its 3'-5' exonuclease activity. Int. J. Cancer 128:40-50, 2011. PMCID: 2946830
Novak, M., Jarrett, S.G., McCorkle, J.R., Mellon, I. and Kaetzel, D.M. (2011) NM23-H1 suppresses metastasis through diverse molecular mechanisms. Naunyn-Schmied.Arch. Pharmacol. 384:433-438, 2011. PMCID: 21448569.
Jarrett, S.G., Novak, M., Harris, N., Mellon, I., Zhang, Q., Arnaud-Dabernat, S., Daniel, J.-Y., Ciesielski, M.J., Fenstermaker, R.A. and Kaetzel, D.M. (2011) The metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis. Cancer Res. 72: 133-143, 2011. PMCID: 22080566
Ganguly, S., Fiore, L.S., Sims, J.T., Friend, J.W., Srinivasan, D., Cibull, M.L., Wang, C., Kaetzel, D.M. and Plattner, R. (2012) Activation of c-Abl and Arg in human melanoma cells promotes survival, proliferation, invasion, and metastasis via distinct molecular pathways. Oncogene 31:1804-1816, 2012. PMCID: 21892207.
Deng, X., Li, Q., Hoff, J., Yang, H., Jin, H., Erfani, S.F., Sharma, C., Zhou, P., Rabinovitz, I., Sonnenberg, A., Yi, A., Zhou, P., Stipp, C.S., Kaetzel, D.M., Hemler, M.E. and Yang, X.H. (2012) Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis. Neoplasia, 14:678-689, 2012. PMCID: 22952421
Jarrett, S., Novak, M., Harris, N., Merlino, G., Slominski, A. and Kaetzel, D. (2012) NM23 deficiency promotes metastasis in a UV radiation-induced mouse model of human melanoma. Clin. Exp. Metastasis, 30:25-36, 2013. PMID: 22699362.
Fiore, L.S., Ganguly, S.S., Sledziona, J., Cibull, M.L., Wang, C., Richards, D.L., Neltner, J.M., Beach, C., McCorkle, J.R., Kaetzel, D.M. and Plattner, R. c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene 33:4508-4520, 2014. PMID: 24096484
McCorkle, J.R., Leonard, M.K., Kraner, S.D., Blalock, E.M., Ma, D., Zimmer, S.G. and Kaetzel, D.M. The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma. Cancer Genomics Proteomics 11:175-194, 2014. PMID: 250483347
Hoff, J.T., Baldwin, L.A., Lefringhouse, J., Zhang, M., Liu, Z., Erfani, S., She, Q.-B., Jia, C., Ueland, F.R., van Nagell, J.R., Wang, C., Xu, M., Kaetzel, D.M., Liu, C., Luo, J., Drapkin, R., Zhou, B. and Yang, X.H. CD151 regulates ovarian tumor growth and progression. Oncotarget 5:12203-12217, 2014. PMID: 25356755
Kaetzel, D.M., Leonard, M.K., Cook, G.S., Novak, M., Jarrett, S.G., Yang, X. and Belkin, A.M. Dual functions of NME1 in suppression of cell motility and enhancement of genomic stability in melanoma. Naunyn-Schmied. Arch. Pharmacol. 388:199-206, 2015. PMCID: 4294989
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