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Drazen B. Zimonjic, Ph.D.

Portait Photo of Drazen Zimonjic
Laboratory of Experimental Carcinogenesis
Staff Scientist
Center for Cancer Research
National Cancer Institute
Building 37, Room 4128C
Bethesda, MD 20892-4262
Phone:  
301-435-7217
Fax:  
301-496-0734
E-Mail:  
drazen_zimonjic@nih.gov

Biography

Dr. Drazen B. Zimonjic received his BS, MS, and PhD from the University of Belgrade in Belgrade, Yugoslavia. He had been a tenured Professor of Biology in the School of Veterinary Medicine of the University of Belgrade before joining, in 1992, the NCI's Laboratory of Biology. Together with Dr. N.C. Popescu he later (1996) co-founded the Molecular Cytogenetic Section in the Laboratory of Experimental Carcinogenesis, where he has been working since as a Staff Scientist. Dr. Zimonjic authored or coauthored three textbooks and over 140 research articles published in peer review journals. His work has been cited in scientific literature over 4,500 times. Dr. Zimonjic received several grants and awards during his career in the University of Belgrade and, in recognition of his work on molecular cytogenetic identification and characterization of recurrent genomic changes in solid tumors and hematological malignancies, was awarded the NIH Merit Award. He is a member or a founding member of a number of scientific societies, serves on editorial board or as a reviewer for several scientific journals and is a (non-resident) member of the Serbian Academy of Sciences and Arts in Belgrade.

Research

Dr. Zimonjic's research interest is identification of genomic alterations associated with the initiation and progression of neoplasia, and their dissection at the chromosomal, molecular and/or functional levels aimed to identification of new genes and new cytological or molecular markers for diagnosis and/or prognosis of neoplastic diseases and, also, of a new potential targets for their therapy.

During the neoplastic process, certain tumor cells acquire resistance to the antiproliferative signaling of transforming growth factor β (TGFβ). Examination of HCC cell line sensitive to TGFβ1 (Hep3B-TS) and its derivative (Hep3B-TR) rendered resistant to TGFβ1 by stepwise exposure to the agent, using SKY and array CGH analysis showed that the acquisition of TGFβ resistance resulted in a loss of TGFβ receptor II (TGFβRII) gene, which occurred when the only apparently normal chromosome 3 in Hep3B-TR cells underwent interstitial microdeletion encompassing the site of the gene. A comparative differential gene expression analysis of the above-mentioned cell lines using an oligonucleotide microarray identified six genes in Hep3BTR cells that are downstream targets of the tumor necrosis factor -TNF gene, suggesting that loss of TGFβRII triggered the activation of the tumor necrosis factor network known to be regulated by the TGFβ1 pathway. Functionally, loss of TGFβRII in cells resistant to TGFβ1 greatly enhanced cell migration and anchorage-independent growth in vitro and also increased in vivo tumorigenicity compared with parental sensitive cells.

Accumulation of DNA damage may play an essential role not only in the process of aging, but also in induction of cellular senescence. The ability of cells to sense and repair DNA damage declines with age. Immunostaining with anti-γ-H2AX antibodies combined with telomere- specific FISH in cells from normal individuals of different age and from patients with premature aging provided evidences that the incidence of DNA double strand breaks increases with the donor's age, and was more pronounced in cells from patients with pathological aging. Overall these findings suggest that increasing inefficiency in these processes may contribute to genome instability associated with aging.

SKY and array-CGH analysis of several cell lines derived from HCC, spontaneously developed in MYC transgenic mice, identified recurrent chromosome rearrangements and genomic imbalances. Among genomic imbalances, partial or complete gain of chromosomes 15 and 19 and loss of chromosomes 4, 9, and 14 were the most common alterations. These alterations are also recurrent in HCC developed in other transgenic mouse models, in mouse spontaneous HCC, and derivative cell lines, as well as in preneoplastic liver lesions induced with chemical carcinogens. Therefore, these results demonstrate selective, nonrandom genomic changes are associated with development of HCC.

Integration of oncogenic viruses is not a random phenomenon because fragile sites (FSs), which frequently correspond to the location of growth-regulatory genes, appear to be preferred genomic targets. FISH analysis of SV 40-immortalized human cells provided evidence of this virus's specific integration at region 1q21.1, which corresponds with the location of a common FS. (FRA1F) Ectopic expression of gene(s) disrupted by viral insertion restored normal growth pattern and senescence.

DLC1 gene - a bona fide tumor suppressor gene that also acts as a metastasis suppressor in several forms of cancer - have been one of Dr. Zimonjic's major focuses ever since this gene's isolation in 1998. Restoration of DLC1 expression was shown to inhibit the dissemination of aggressive liver tumor cells to distant organs. This process is associated with reduction of RhoA GTPase activity, cytoskeleton alterations, down regulation of osteopontin and matrix metalloproteinase-9 expression, which are highly up regulated in most primary liver tumors with associated metastases. DLC1 is also recurrently down regulated or inactivated in multiple myeloma (MM) cells. Re-expression of DLC1 inhibited MM cell invasion and migration, reduced RhoA activity and resulted in reorganization of actin cytoskeleton.

DLC1-mediated suppression of cell migration and invasion is of significant importance as the two processes are instrumental in the myeloma cell movement within the bone morrow and metastasis to secondary sites. Among several potential binding partners of DLC1 identified by a yeast two-hybrid screening, S100A10 and α-catenin proteins have been later confirmed in human cells as DLC1-interacting proteins. S100A10 is an inflammatory protein and a key cell surface receptor for plasminogen that regulates pericellular proteolysis and tumor cells ability to form metastases. In addition to identifying respective binding sites in both proteins, the study demonstrated that DLC1 interaction with S100A10 resulted in attenuation of plasminogen activation accompanied by inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells.

Malignant transformation and tumor progression to metastasis are often associated with changes in cytoskeleton organization and cell-cell adhesion. Interaction of DLC1 with α-catenin resulted in a reduction of Rho GTP levels at plasma membraneand increased E-cadherin's mobility; it affected actin organization and stabilized adherens junctions (AJs) instrumental for maintaining stable tissue architecture. These results unraveled a new mechanism through which DLC1 exerts its strong oncosuppressive effect in metastatic prostate carcinoma cells, by positively influencing AJs stability.

This page was last updated on 3/5/2013.