Lyuba Varticovski, M.D.
Our laboratory pioneered the analysis of global chromatin landscape using DnaseI hypersensitive sites (sites in the entire mammalian genome that are accessible to interaction with regulatory elements at any time) in normal and cancer cells, and their changes in response to drugs and activation of nuclear receptors. We adapted this method to probe global chromatin modifications during differentiation of stem cells into osteogenic lineage, a process that requires glucocorticoids, in characterizing metastatic potential, and acquisition of drug resistance.
1) cancer biology, 2) chromatin biology, 3) nuclear receptors, 4) anticancer drug
development, 5) bone differentiation
Over the last 20 years I have worked on drug development, optimizing anticancer therapies by understanding the synergy and antagonism of drugs when conventional anticancer drugs with are combined with molecular targeted agents, and on mechanisms of drug resistance. Identification of cancer stem cells has been useful in defining a subpopulation of cells responsible for drug resistance and tumor recurrence. However, in order to develop more effective therapies for cancer, we need a better understanding of stem cell biology. We recently came to appreciate that the accessibility of transcription factors (TFs) to DNA ultimately controls stemness, reprogramming and differentiation. The Laboratory of Receptor Biology and Gene Expression (LRBGE) under the direction of Gordon Hager pioneered the study of changes in the global unbiased chromatin landscape (i.e., all sites in the genome that are accessible to interaction with proteins at any time) in response to activation of glucocorticoids and other nuclear receptors. In-depth bioinformatic annotation to the mammalian genome provides an unbiased view of changes in accessibility for all regulatory elements in any cell type at any given time. These studies provide information that is not possible to obtain by other techniques, such as ChIP. We are using DHS-seq to probe chromatin modifications in iPS and mesenchymal stem cells differentiated to osteogenic lineage, a process that requires glucocorticoids. These studies have led to an appreciation of novel pathways involved in stem cell differentiation and osteogenesis. We have also uncovered novel pathways involved in metastatic progression and acquisition of drug resistance. Our current studies involve development of a bioinformatic method that allow linking the novel information on global changes in Dnase hypersensitivity to miRNA, gene expression and other cancer genome data.
- Scientific Reports. 9(1):516: Nature 1-12, 2019. [ Journal Article ]
- Sci Rep.. 2019. [ Journal Article ]
- Sci Rep. 2: 937-40, 2012. [ Journal Article ]
Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure.PLoS Genet. 10(9): e1004613, 2014. [ Journal Article ]
A quantitative high-throughput assay for detection of biologically active endocrine-disrupting chemicals in water.In: Aquananotechnology: Global Prospects. DE Reisner and T Pradeep, eds: CRC Press 2014. [ Book Chapter ]
Dr. Varticovski was born in Siberia, Russia, where she completed undergraduate and first-year medical school. She received her M.D. degree from the University of Valle, Colombia. After a 2-year research fellowship with Max Wintrobe and James Kushner at the Univeristy of Utah and training in internal medicine at Albany Medical College, NY, she completed her fellowship in hematology and oncology at the New England Medical Center in Boston, MA. She joined the laboratory of Lewis C. Cantley in 1985 where she shared in the discovery and biochemistry of phosphatidylinositol 3-kinase (PI 3-Kinase). She held a clinical staff position in hematology and oncology at a Tufts University-affiliated hospital in Boston, MA, from 1989 to 2001. She studied the role of PI 3-kinase in protein-tyrosine kinase-mediated signal transduction, drug resistance and vesicular trafficking at Tufts Medical School where she rose to the rank of Associate Professor. Dr. Varticovski is board-certified in internal medicine and hematology and board-eligible in oncology. She is a member of the American Society for Hematology, American Society of Clinical Oncology and the American Association for Cancer Research.
In 2003, she joined the National Cancer Institute (NCI) in Bethesda, Maryland as a Staff Clinician and was subsequently promoted to Associate Scientist. At the NCI Center for Cancer Research, Dr. Varticovski has directed the Preclinical Models Strategy Team, Molecular Targeting Unit, Lung Cancer Stem Cell Core, and participated in clinical trials at the NIH Clinical Center for patients with drug-resistant tumors. She is currently a member of the Laboratory of Receptor Biology and Gene Expression, under the direction of Dr. Gordon Hager, where she focuses on genome-wide characterization of normal and cancer stem cells and their differentiation into osteogenic lineage.