Dr. Costes laboratory specializes on various aspect of computational biology.
Areas of expertise:
- Radiation biology
- Modeling and radiation system biology
- Three-dimensional microscopy
- High-content image analysis
Three-dimensional human mammary epithelial cell cultures known to mimic human breast in vitro are the primary biological systems used in the lab. These systems have been used to quantify the effect of ionizing radiation at the DNA and extra-cellular level. The lab is currently involved with two multi-investigators interdisciplinary projects:
NASA Specialized Center of Research (NSCOR)
1. Modeling DNA damage patterns in human cells exposed to cosmic radiation.
The spatial distribution of DNA damage measured by markers such as phosphorylated histone H2AX or p53 binding protein 1 (53BP1) were compared to theoretical predictions from a mathematical model developed in our lab. These comparisons led to the conclusion that damages are not detected at their original site of damage, but instead at specific location in the nucleus. Our lab is currently investigating if this is the result of nuclear reorganization following ionizing radiation or the clustering of DNA damage into repair centers. Reorganization of damages into specific regions in the nucleus has important consequences for evaluating risk of cosmic rays on human, a topic of interest for our lab as well.
2. Modeling disruption of organized cell population following ionizing radiation.
We are currently establishing an agent-based model that mimics cell behavior when grown as monolayer or in three-dimension. These in silico cell cultures are currently being used to test the impact of radiation on cell death, cell proliferation and how this translates at the phenotype level.
DOE low-dose radiation Program. This project evaluates chromatin modifications following exposure to low dose of low-LET radiation. We are working under the current hypothesis that DNA damage elicits chromatin modification necessary for DNA repair which can lead in some cases to permanent changes in the epigenetic status of a cell. Dr. Costes group focuses on characterizing by image analysis permanent changes in chromatin organization in primary and immortalized human mammary epithelial cells (HMEC) and fibroblasts at different time points after low and high dose irradiation. This type of studies offers an alternative mechanism for explaining persistent phenotype acquired following exposure to ionizing radiation such as Epithelial-Mesenchymal Transition (EMT) or Genomic Instability (GI).
Mukhopadhya R., Costes S.V., Bazarov A., Hines W.C., Barcellos-Hoff M.H., Yaswen P. Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies. Breast Cancer Research (2010).
Costes S.V., Chiolo I., Pluth J.M., Barcellos-Hoff M.H. and Jakob B. Spatiotemporal characterization of ionizing radiation induced DNA damage foci and their relation to chromatin organization. Mutat Res (2010).
Ghajar C.M., Kachgal S., Kniazeva E., Mori H., Costes S.V., George S.C. and Putnam A.J. Mesenchymal cells stimulate capillary morphogenesis via distinct proteolytic mechanisms. Exp Cell Res (2010).
Ponomarev A.L., Costes S.V., Cucinotta F.A.Stochastic properties of radiation-induced DSB: DSB distributions in large scale chromatin loops, the HPRT gene and within the visible volumes of DNA repair foci, Int J Radiat Biol. 2008 Nov;84(11):916-29.
Maxwell C.A., Fleisch M.C., Costes S.V., Erickson A.C., Boissiere A., Gupta R., Ravani S.A., Parvin B., Barcellos-Hoff M.H. Targeted and non-targeted effects of ionizing radiation that impact genomic instability. Cancer Res. 2008 Oct 15;68(20):8304-11.
Barkan D., Kleinman H., Simmons J.L., Asmussen H., Kamaraju A.K., Hoenorhoff M.J., Liu Z.Y., Costes S.V., Cho E.H., Lockett S., Khanna C., Chambers A.F., Green J.E. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 2008 Aug 1;68(15):6241-50.
Andarawewa K.L., Erickson A.C., Chou W.S., Costes S.V., Gascard P., Mott J.D., Bissell M.J., Barcellos-Hoff M.H.. Ionizing Radiation Predisposes Nonmalignant Human Mammary Epithelial Cells to Undergo Transforming Growth Factor Induced Epithelial to Mesenchymal Transition. Cancer Res. 2007 Sep 15;67(18):8662-70.
Costes S.V., Ponomarev A., Chen J.L., Nguyen D., Cucinotta F.A., Barcellos-Hoff M.H. Image-based model reveals dynamic redistribution of DNA damage into nuclear sub-domains, PLoS Comput Biol. 2007 Aug 3;3(8):e155. (Made the cover for the journal for that month).
Fleisch M.C., Maxwell C.A., Kuper C.K., Brown E.T., Barcellos-Hoff M.H., Costes, S.V. Intensity-based signal separation algorithm for accurate quantification of clustered centrosomes in tissue sections. Microsc Res Tech 69 (12): 964-972 (Dec. 2006).
Costes, S. V., A. Boissière, S. Ravani, R. Romano, B. Parvin and M. H. Barcellos-Hoff. Imaging features that discriminate between high and low LET radiation-induced foci in human fibroblasts." Radiat Res,165 (5): 505-515 (May 2006).
Barcellos-Hoff, M. H. and S. V. Costes. A systems biology approach to multicellular and multi-generational radiation responses. Mutation Research 597 (1-2): 32-38 (May 11, 2006).
Daelemans, D., Costes, S. V., Lockett, S. & Pavlakis, G. N. Kinetic and molecular analysis of nuclear export factor CRM1 association with its cargo in vivo. Mol Cell Biol 25, 728-39 (2005).
Costes, S. V. et al. Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys J 86, 3993-4003 (2004).
Costes, S. et al. Large-mutation spectra induced at hemizygous loci by low-LET radiation: evidence for intrachromosomal proximity effects. Radiat Res 156, 545-57 (2001).
Costes, S., Streuli, C. H. & Barcellos-Hoff, M. H. Quantitative image analysis of laminin immunoreactivity in skin basement membrane irradiated with 1 GeV/nucleon iron particles. Radiat Res 154, 389-97 (2000).