Jack Lawler, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-1694
Fax: (617) 667-3591


Jack Lawler, PhD

Beth Israel Deaconess Medical Center


  • Professor, Pathology, Harvard Medical School
  • Vice-Chair for Research, Pathology, Beth Israel Deaconess Medical Center


  • Member, Center Scientific Council

Research Abstract

Thrombospondin-1 (TSP-1) and -2 are extracellular, calcium-binding proteins that regulate cellular phenotype by orchestrating the assembly of multiprotein complexes on the cell surface. These complexes include CD36, transforming growth factor beta, proteoglycans, integrins and integrin associated proteins. Thrombospondin-1 on the cell surface inhibits (1) proliferation of endothelial cells and tumor cells in vitro, (2) endothelial cell migration and angiogenesis, and (3) the growth of experimental and naturally occurring tumors in vivo. To establish a role for TSP-1 in the progression of spontaneously occurring tumors that arise at orthotopic sites in vivo, we have crossed mice that are deficient in TSP-1 with mice that are deficient in p53. Mice that lack TSP-1 exhibit decreased survival and altered tumor specturm. Consistent with these observations, overexpression of TSP-1 inhibits tumor growth and angiogenesis. In addition, systemic injection of recombinant type 1 repeats of TSP-1, designated 3TSR, inhibits the growth of experimental tumors formed from breast, colon, pancreatic, skin and ovarian cancer cells. 3TSR is particularly active in an orthotopic model of advance stage ovarian cancer with treated mice showing tumor regression and greatly increased survival in an intervention trial. Survival is further enhanced when 3TSR is combined with chemotherapy. Current research focuses on the development of a therapeutic form of 3TSR that can be used in the clinic.


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  • Sims JN, Lawler J. Thrombospondin-1-Based Antiangiogenic Therapy. 2015; 31:366-70. PubMed
  • Russell S, Duquette M, Liu J, Drapkin R, Lawler J, Petrik J. Combined therapy with thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer. FASEB J. 2015; 29:576-88. PubMed
  • Choi SH, Tamura K, Khajuria RK, Bhere D, Nesterenko I, Lawler J, Shah K. Antiangiogenic variant of TSP-1 targets tumor cells in glioblastomas. Mol Ther 2015; 23:235-43. PubMed
  • Lopez-Dee ZP, Chittur SV, Patel H, Chinikaylo A, Lippert B, Patel B, Lawler J, Gutierrez LS. Thrombospondin-1 in a Murine Model of Colorectal Carcinogenesis. PLoS ONE 2015; 10:e0139918. PubMed
  • Sadow PM, Priolo C, Nanni S, Karreth FA, Duquette M, Martinelli R, Husain A, Clohessy J, Kutzner H, Mentzel T, Carman CV, Farsetti A, Henske EP, Palescandolo E, Macconaill LE, Chung S, Fadda G, Lombardi CP, De Angelis AM, Durante O, Parker JA, Pontecorvi A, Dvorak HF, Fletcher C, Pandolfi PP, Lawler J, Nucera C. Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment. Journal of the National Cancer Institute 2014. PubMed
  • Duquette M, Nadler M, Okuhara D, Thompson J, Shuttleworth T, Lawler J. Members of the thrombospondin gene family bind stromal interaction molecule 1 and regulate calcium channel activity. Matrix Biol 2014. PubMed
  • Dews M, Tan GS, Hultine S, Raman P, Choi J, Duperret EK, Lawler J, Bass A, Thomas-Tikhonenko A. Masking epistasis between MYC and TGF-β pathways in antiangiogenesis-mediated colon cancer suppression. Journal of the National Cancer Institute 2014; 106:dju043. PubMed
  • Qin L, Zhao D, Xu J, Ren X, Terwilliger EF, Parangi S, Lawler J, Dvorak HF, Zeng H. The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood 2013; 121:2154-64. PubMed
  • Duquette M, Sadow PM, Lawler J, Nucera C. Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAF(V600E): New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment. Front Endocrinol (Lausanne) 2013; 4:189. PubMed
  • Shaik S, Nucera C, Inuzuka H, Gao D, Garnaas M, Frechette G, Harris L, Wan L, Fukushima H, Husain A, Nose V, Fadda G, Sadow PM, Goessling W, North T, Lawler J, Wei W. SCF(β-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. J Exp Med 2012; 209:1289-307. PubMed
  • Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Sargent MA, Blair NS, Lynch KA, Okada T, Aronow BJ, Osinska H, Prywes R, Lorenz JN, Mori K, Lawler J, Robbins J, Molkentin JD. A thrombospondin-dependent pathway for a protective ER stress response. Cell 2012; 149:1257-68. PubMed
  • Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med 2012; 2:a006627. PubMed
  • Seymour KA, Sadowitz B, Stein JJ, Lawler J, Maier KG, Gahtan V. Vascular smooth muscle cell migration induced by domains of thrombospondin-1 is differentially regulated. Am J Surg 2011. PubMed
  • Adams JC, Lawler J. The thrombospondins. Cold Spring Harb Perspect Biol 2011; 3:a009712. PubMed
  • Olerud J, Mokhtari D, Johansson M, Christoffersson G, Lawler J, Welsh N, Carlsson PO. Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function. Diabetes 2011; 60:1946-54. PubMed
  • Xie L, Duncan MB, Pahler J, Sugimoto H, Martino M, Lively J, Mundel T, Soubasakos M, Rubin K, Takeda T, Inoue M, Lawler J, Hynes RO, Hanahan D, Kalluri R. Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner. Proc Natl Acad Sci U S A 2011; 108:9939-44. PubMed
  • Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 2011; 208:1083-92. PubMed
  • Kazerounian S, Duquette M, Reyes MA, Lawler JT, Song K, Perruzzi C, Primo L, Khosravi-Far R, Bussolino F, Rabinovitz I, Lawler J. Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase. Blood 2011. PubMed
  • Nucera C, Lawler J, Parangi S. BRAF(V600E) and microenvironment in thyroid cancer: a functional link to drive cancer progression. Cancer Res 2011; 71:2417-22. PubMed
  • Nucera C, Nehs MA, Nagarkatti SS, Sadow PM, Mekel M, Fischer AH, Lin PS, Bollag GE, Lawler J, Hodin RA, Parangi S. Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer. Oncologist 2011; 16:296-309. PubMed
  • Tan K, Lawler J. The structure of the Ca²+-binding, glycosylated F-spondin domain of F-spondin - A C2-domain variant in an extracellular matrix protein. BMC Struct. Biol. 2011; 11:22. PubMed
  • Nucera C, Lawler J, Hodin R, Parangi S. The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? 2011; 1:751-6. PubMed
  • Ezzie ME, Piper MG, Montague C, Newland CA, Opalek JM, Baran C, Ali N, Brigstock D, Lawler J, Marsh CB. Thrombospondin-1 Deficient Mice Are Not Protected from Bleomycin-Induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol 2010. PubMed
  • Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C, Puxeddu E, Finn S, Jarzab B, Hodin RA, Pontecorvi A, Nose V, Lawler J, Parangi S. B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression. Proc Natl Acad Sci U S A 2010; 107:10649-54. PubMed
  • Lawler J. Megakaryocytes join the war on cancer. Blood 2010; 115:4326-7. PubMed
  • Tan K, Lawler J. The interaction of Thrombospondins with extracellular matrix proteins. J Cell Commun Signal 2010; 3:177-87. PubMed
  • Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 2009; 139:380-92. PubMed
  • Nucera C, Nehs MA, Mekel M, Zhang X, Hodin R, Lawler J, Nose V, Parangi S. A novel orthotopic mouse model of human anaplastic thyroid carcinoma. Thyroid 2009; 19:1077-84. PubMed
  • Zhang X, Kazerounian S, Duquette M, Perruzzi C, Nagy JA, Dvorak HF, Parangi S, Lawler J. Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level. FASEB J 2009; 23:3368-76. PubMed
  • Tan K, Duquette M, Joachimiak A, Lawler J. The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding. FASEB J. 2009; 23:2490-501. PubMed
  • Velasco P, Huegel R, Brasch J, Schröder JM, Weichenthal M, Stockfleth E, Schwarz T, Lawler J, Detmar M, Lange-Asschenfeldt B. The angiogenesis inhibitor thrombospondin-1 inhibits acute cutaneous hypersensitivity reactions. J Invest Dermatol 2009; 129:2022-30. PubMed
  • Lawler J. Introduction to the tumour microenvironment review series. J Cell Mol Med 2009; 13:1403-4. PubMed
  • Ren B,Song K,Parangi S,Jin T,Ye M,Humphreys R,Duquette M,Zhang X,Benhaga N,Lawler J,Khosravi-Far R. A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res 2009; 69:3856-65. PubMed
  • Sun J,Hopkins BD,Tsujikawa K,Perruzzi C,Adini I,Swerlick R,Bornstein P,Lawler J,Benjamin LE. Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina. Am J Physiol Heart Circ Physiol 2009; 296:H1344-51. PubMed
  • Yee KO, Connolly CM, Duquette M, Kazerounian S, Washington R, Lawler J. The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat 2009; 114:85-96. PubMed
  • Greenaway J, Henkin J, Lawler J, Moorehead R, Petrik J. ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer. Mol Cancer Ther 2009; 8:64-74. PubMed
  • Posey KL, Hankenson K, Veerisetty AC, Bornstein P, Lawler J, Hecht JT. Skeletal Abnormalities in Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, and Type IX Collagen. Am J Pathol 2008; 172:1664-74. PubMed
  • Tan K, Duquette M, Liu JH, Shanmugasundaram K, Joachimiak A, Gallagher JT, Rigby AC, Wang JH, Lawler J. Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain. J Biol Chem 2007; 283:3932-41. PubMed
  • Punekar S, Zak S, Kalter VG, Dobransky L, Punekar I, Lawler JW, Gutierrez LS. Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease. Pathobiology 2008; 75:9-21. PubMed
  • Ali NA, Gaughan AA, Orosz CG, Baran CP, McMaken S, Wang Y, Eubank TD, Hunter M, Lichtenberger FJ, Flavahan NA, Lawler J, Marsh CB. Latency associated peptide has in vitro and in vivo immune effects independent of TGF-beta1. PLoS ONE 2008; 3:e1914. PubMed
  • Daniel C, Schaub K, Amann K, Lawler J, Hugo C. Thrombospondin-1 is an endogenous activator of TGF-beta in experimental diabetic nephropathy in vivo. Diabetes 2007; 56:2982-9. PubMed
  • Zhang X, Lawler J. Thrombospondin-based antiangiogenic therapy. Microvasc Res 2007; 74:90-9. PubMed
  • Chen FH, Herndon ME, Patel N, Hecht JT, Tuan RS, Lawler J. Interaction of cartilage oligomeric matrix protein/thrombospondin 5 with aggrecan. J Biol Chem 2007; 282:24591-8. PubMed
  • Budhani F, Leonard KA, Bergdahl A, Gao J, Lawler J, Davis EC. Vascular response to intra-arterial injury in the thrombospondin-1 null mouse. J Mol Cell Cardiol 2007; 43:210-4. PubMed
  • Zhang X, Xu J, Lawler J, Terwilliger E, Parangi S. Adeno-associated virus-mediated antiangiogenic gene therapy with thrombospondin-1 type 1 repeats and endostatin. Clin Cancer Res 2007; 13:3968-76. PubMed
  • Zhang X, Connolly C, Duquette M, Lawler J, Parangi S. Continuous administration of the three thrombospondin-1 type 1 repeats recombinant protein improves the potency of therapy in an orthotopic human pancreatic cancer model. Cancer Lett 2006; 247:143-9. PubMed
  • Greenaway J, Lawler J, Moorehead R, Bornstein P, Lamarre J, Petrik J. Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1). J Cell Physiol 2007; 210:807-18. PubMed
  • Zwicker JI, Peyvandi F, Palla R, Lombardi R, Canciani MT, Cairo A, Ardissino D, Bernardinelli L, Bauer KA, Lawler J, Mannucci P. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size. Blood 2006; 108:1280-3. PubMed
  • Bonnefoy A, Daenens K, Feys HB, De Vos R, Vandervoort P, Vermylen J, Lawler J, Hoylaerts MF. Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13. Blood 2006; 107:955-64. PubMed
  • Tan K, Duquette M, Liu JH, Zhang R, Joachimiak A, Wang JH, Lawler J. The structures of the thrombospondin-1 N-terminal domain and its complex with a synthetic pentameric heparin. Structure 2006; 14:33-42. PubMed
  • Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J. Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J Biol Chem 2005; 280:32655-61. PubMed
  • Zhang X, Galardi E, Duquette M, Lawler J, Parangi S. Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model. Clin Cancer Res 2005; 11:5622-30. PubMed
  • Frangogiannis NG, Ren G, Dewald O, Zymek P, Haudek S, Koerting A, Winkelmann K, Michael LH, Lawler J, Entman ML. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation 2005; 111:2935-42. PubMed
  • Zhang X, Galardi E, Duquette M, Delic M, Lawler J, Parangi S. Antiangiogenic treatment with the three thrombospondin-1 type 1 repeats recombinant protein in an orthotopic human pancreatic cancer model. Clin Cancer Res 2005; 11:2337-44. PubMed
  • Sund M, Hamano Y, Sugimoto H, Sudhakar A, Soubasakos M, Yerramalla U, Benjamin LE, Lawler J, Kieran M, Shah A, Kalluri R. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc Natl Acad Sci U S A 2005; 102:2934-9. PubMed
  • Short SM, Derrien A, Narsimhan RP, Lawler J, Ingber DE, Zetter BR. Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins. J Cell Biol 2005; 168:643-53. PubMed
  • Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 2005; 120:421-33. PubMed
  • Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D'Amato RJ, Kerbel RS. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 2005; 7:101-11. PubMed
  • Calzada MJ, Annis DS, Zeng B, Marcinkiewicz C, Banas B, Lawler J, Mosher DF, Roberts DD. Identification of novel beta1 integrin binding sites in the type 1 and type 2 repeats of thrombospondin-1. J Biol Chem 2004; 279:41734-43. PubMed
  • Yee KO, Streit M, Hawighorst T, Detmar M, Lawler J. Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol 2004; 165:541-52. PubMed
  • Niu Q, Perruzzi C, Voskas D, Lawler J, Dumont DJ, Benjamin LE. Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1. Cancer Biol Ther 2004; 3:402-5. PubMed
  • Cursiefen C, Masli S, Ng TF, Dana MR, Bornstein P, Lawler J, Streilein JW. Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis. Invest Ophthalmol Vis Sci 2004; 45:1117-24. PubMed
  • Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, Sudhakar A, Kalluri R. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 2004; 64:1570-4. PubMed
  • Wang S, Wu Z, Sorenson CM, Lawler J, Sheibani N. Thrombospondin-1-deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia-mediated vessel obliteration. Dev Dyn 2003; 228:630-42. PubMed
  • Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 2003; 100:12917-22. PubMed
  • Gutierrez LS, Suckow M, Lawler J, Ploplis VA, Castellino FJ. Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model. Carcinogenesis 2003; 24:199-207. PubMed
  • Tan K, Duquette M, Liu JH, Dong Y, Zhang R, Joachimiak A, Lawler J, Wang JH. Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication. J Cell Biol 2002; 159:373-82. PubMed
  • Agah A, Kyriakides TR, Lawler J, Bornstein P. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 2002; 161:831-9. PubMed
  • Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 2002; 6:1-12. PubMed
  • Ndishabandi D, Duquette C, Billah GE, Reyes M, Duquette M, Lawler J, Kazerounian S. Thrombospondin-1 Modulates Actin Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro. Discoveries (Craiova) 2015. PubMed