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, 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. 2008; 13(5):420-31.
02. 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. 2009; 459(7250):1126-30.
03. Zaslavsky A, Baek KH, Lynch RC, Short S, Grillo J, Folkman J, Italiano JE Jr, Ryeom S. Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood. 2010; 115(22):4605-13.
04. Minami T, Jiang S, Schadler K, Suehiro J, Osawa T, Oike Y, Miura M, Naito M, Kodama T, Ryeom S. The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases. Cell Reports. 2013; 4(4):709-23.
05. Baek KH, Bhang D, Zaslavsky A, Wang LC, Vachani A, Kim CF, Albelda SM, Evan GI, Ryeom S. Thrombospondin-1 mediates oncogenic Ras-induced senescence in premalignant lung tumors. The Journal of Clinical Investigation. 2013; 123(10):4375-89.
06. Zaslavsky A, Chou ST, Schadler K, Lieberman A, Pimkin M, Kim YJ, Baek KH, Aird WC, Weiss MJ, Ryeom S. The calcineurin-NFAT pathway negatively regulates megakaryopoiesis. Blood. 2013; 121(16):3205-15.
07. Lee JH, Bhang DH, Beede A, Huang TL, Stripp BR, Bloch KD, Wagers AJ, Tseng YH, Ryeom S, Kim CF. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell. 2014; 156(3):440-55.
08. Schadler KL, Crosby EJ, Zhou AY, Bhang DH, Braunstein L, Baek KH, Crawford D, Crawford A, Angelosanto J, Wherry EJ, Ryeom S. Immunosurveillance by antiangiogenesis: tumor growth arrest by T cell-derived thrombospondin-1. Cancer Research. 2014; 74(8):2171-81.
09. Zhou AY, Ryeom S. Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. Molecular Cancer Research: MCR. 2014; 12(11):1663-76.
10. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, 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. 2010 Nov 16;18(5):485-98. doi: 10.1016/j.ccr.2010.10.002. Epub 2010 Oct 28. Erratum in: Cancer Cell. 2010 Dec 14;18(6):696.
Allyson Lieberman - Graduate Student
Bang-jin Kim - Postdoctoral Researcher
Caroline Kitzmiller - Administrative Coordinator
Jacob Till - Graduate Student
Jaeyoung Shin - Undergraduate Student
Kathy Zhang - Undergraduate Student
Kerry Roby - Graduate Student
Prince Addai - Undergraduate Student
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