My lab is interested in understanding the molecular mechanisms that regulate the tumor microenvironment with a particular focus on the vasculature.
Cancer, angiogenesis, tumor suppressors, calcineurin signaling, senescence, immune surveillance
The overarching goal of my laboratory is to understand how the tumor microenvironment is assembled and maintained, with particular focus on the generation and maintenance of the tumor blood supply – the process of tumor angiogenesis. Tumor angiogenesis is a dynamic process involving continuous elaboration and remodeling of blood vessels in the tumor microenvironment. It is driven by the precocious production of various angiogenic factors of which the best characterized is VEGF, an endothelial mitogen whose regulation and downstream effectors have been the focus of intense investigation for over a decade. However, angiogenesis is under constant restraint by a variety of endogenous inhibitors, and it has become clear that modulation of these inhibitors also plays a critical role in tumor angiogenesis but the mechanisms by which they do so are far less well understood.
Figure: Down syndrome and normal induced pluripotent stem cells (iPS) cells. Teratomas derived from Down syndrome iPS cells (top) show suppression of tumor angiogenesis as compared to those derived from normal iPS cells (bottom) as indicated by CD31 staining (red).
My laboratory is particularly interested in understanding how angiogenesis inhibitors act to limit endothelial cell activation and angiogenesis, how they are regulated by tumor suppressors and oncogenes, and how they might be used therapeutically to treat cancers.
Rotation projects include:
i) Understanding why Down syndrome individuals are protected against cancer and the role of the calcineurin inhibitor, DSCR1 in suppressing VEGF-mediated angiogenesis;
ii) Identifying new cell extrinsic tumor suppressor functions of p53 and p19ARF: regulation of the endogenous angiogenesis inhibitors thrombopsondin-1 and endostatin;
iii) Investigating a novel role for the endogenous angiogenesis inhibitor thrombospondin-1 in mediating oncogene-induced senescence;
iv) Immune surveillance and the role of the endogenous angiogenesis inhibitors thrombospondin-1 and endostatin in tumor immunity.
Keri Stewart, Ph.D.
Alexander Zaslavsky, Ph.D.
Dong Ha Bhang, Ph.D.
Zaslavsky A, Baek KH, Lynch R, Short S, Grillo J, Folkman J, Italiano JE Jr., Ryeom, S: Platelet-derived thrombospondin-1 (TSP-1) is a critical negative regulator and potential biomarker of angiogenesis. Blood 115: 4605-4613, 2010.
Lee YJ, Koch M, Karl D, Torres-Collado AX, Namali T, Fernando NT, Rothrock C, Kuruppu D, Ryeom S, Iruela-Arispe ML, Yoon SS: Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1. Cancer Res. 70: 948-956, 2010.
Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park, IH, Yoon SS, Minami T, Reeves R, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S: Down syndrome suppression of tumor growth and the role of the calcineurin inhibitor DSCR1. Nature 459: 1126-1130, 2009.
Ryeom S, Baek KH, Zaslavsky A: Down's syndrome: protection against cancer and the therapeutic potential of DSCR1. Future Oncology 5(8): 1185-1188, 2009.
Minami T, Yano K, Miura M, Kobayashi M, Suehiro J, Reid PC, Hamakubo T, Ryeom S, Aird WC, Kodama T: The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice. J. Clin. Invest. 119: 2257-2570, 2009.
Ryeom S, Rioth M, Lynch R, Baek KH, Birsner A, Yoon, SS, McKeon F: Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 13: 420-431, 2008.
Italiano JE Jr, Richardson JL, Patel-Hett S, Bttinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL: Angiogenesis is regulated by a novel mechanism: Pro- and anti-angiogenic 3 proteins are organized into separate platelet alpha-granules and differentially released. Blood 111: 1227-1233, 2008.
Fernando NT, Koch M, Rothrock C, Gollogly LK, D'Amore PA, Ryeom S, Yoon SS: Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by upregulation of multiple pro-angiogenic proteins. Clin. Cancer Res. 14: 1529-1539, 2008.
Beaudry P, Hida Y, Udagawa T, Alwayn IP, Greene AK, Arsenault D, Folkman J, Heymach JV, Ryeom S, Puder M: Endothelial progenitor cells contribute to accelerated liver regeneration. J. Ped. Res. 42: 1190-1198, 2006.
Giuriato S, Ryeom S, Fan A, Bachireddy P, Lynch R, Rioth M, Kopelman AM, Passegue E, Tang F, Folkman J, Felsher DW: Sustained regression of tumors upon MYC inactivation requires p53 or TSP-1 to reverse the angiogenic switch. Proc. Natl. Acad. Sci. 103: 16266-16271, 2006.
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Last updated: 06/11/2015
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