The past decade has seen a growing appreciation that cancers are not just clonal expansions of tumor cells but aberrant tissues, comprising many distinct cells types. From this has evolved the notion that effective cancer therapies should combine agents that target not only the tumor cells themselves but also the tumor microenvironment. 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.
The Ryeom Laboratory
My laboratory is particularly interested in understanding how angiogenesis inhibitors act to limit endothelial cell activation and angiogenesis, and how they might be used therapeutically to treat cancers. Specific 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.
01. Ryeom S, Greenwald RJ, Sharpe AH, McKeon F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nature Immunology 4(9):874-81. 2003. PMID: 12925851.
02. Giuriato S, Ryeom S, Fan AC, Bachireddy P, Lynch RC, Rioth MJ, van Riggelen J, Kopelman AM, Passegué E, Tang F, Folkman J, Felsher DW. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proceedings of the National Academy of Sciences USA 103(44):16266-71. 2006. PMID: 17056717; PMCID: PMC1637571.
03. Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, Birsner A, Yoon SS, McKeon F. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 13(5):420-31. 2008. PMID: 18455125.
04. Beaudry P, Nilsson M, Rioth M, Prox D, Poon D, Xu L, Zweidler-Mckay P, Ryan A, Folkman J, Ryeom S, Heymach J. Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. Molecular Cancer Therapy 7(2):418-24. 2008. PMID: 18245671.
05. Minami T, Yano K, Miura M, Kobayashi M, Suehiro J, Reid PC, Hamakubo T, Ryeom S, Aird WC, Kodama T. Vascular Bed-Specific Regulation of the Short Isoform of Down Syndrome Critical Region-1 in Inflammation. Journal of Clinical Oncology 119(8):2257-70. PMID: 19620774; PMCID: PMC2719921.
06. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459(7250):1126-30. 2009. PMID: 19458618; PMCID: PMC2724004.
07. Lee YJ, Koch M, Karl D, Torres-Collado AX, 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 Research 70(3):948-56. 2010. PMID: 20103648.
08. Zaslavsky A, Chen C, Grillo J, Baek KH, Holmgren L, Yoon SS, Folkman J and Ryeom S. Regional Control of Tumor Growth. Molecular Cancer Research 8: 1198-206. 2010. PMID: 20736295
09. Zaslavsky A, Baek KH, Lynch RC, Short S, Grillo J, Folkman J, Italiano JE, Ryeom S. Platelet-derived thrombospondin-1 (TSP-1) is a critical negative regulator and potential biomarker of angiogenesis. Blood 115:4605-13. 2010. PMID: 20086246; PMCID: PMC2881490.
10. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Erika Crosby E, Ryeom S; Felsher DW. CD4+ T-cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18(5):485-98. 2010. PMID: 21035406.
Allyson Lieberman - Graduate Student
Bang-jin Kim - Postdoctoral Researcher
Caroline Kitzmiller - Administrative Coordinator
Evan Jonokuchi - Undergraduate Student
Jacob Till - Graduate Student
Jaeyoung Shin - Undergraduate Student
Kathy Zhang - Undergraduate Student
Katie Sturgeon - Postdoctoral Researcher
Kerry Roby - Graduate Student
Prince Addai - Undergraduate Student
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