Jack Lawler, PhD

Beth Israel Deaconess Medical Center

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


jlawler@bidmc.harvard.edu

Jack Lawler, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Professor, Pathology, Harvard Medical School
  • Director, Division of Cancer Biology and Angiogenesis, Pathology, Beth Israel Deaconess Medical Center

DF/HCC ASSOCIATIONS

  • 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 recombinent type 1 repeats of TSP-1 inhibits the growth of tumors formed from the subcutaneous injection of B16F10 melanoma cells. These data indicate that tumor growth is inversely proportional to TSP-1 protein expression and that down-regulation of TSP-1 is involved in tumor progression.

Publications

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  • 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
  • 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
  • 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-硫 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(硫-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
  • Nucera C, Lawler J, Parangi S. BRAFV600E and Microenvironment in Thyroid Cancer: A Functional Link to Drive Cancer Progression. Cancer Res 2011; 71:2417-22. 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, 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
  • Nucera C, Lawler J, Hodin R, Parangi S. The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? 2011; 1:751-6. 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
  • Lawler J. Introduction to the tumour microenvironment review series. J Cell Mol Med 2009; 13:1403-4. 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
  • 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
  • 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
  • Olerud J, Johansson M, Lawler J, Welsh N, Carlsson PO. IMPROVED VASCULAR ENGRAFTMENT AND GRAFT FUNCTION FOLLOWING INHIBITION OF THE ANGIOSTATIC FACTOR THROMBOSPONDIN-1 IN MOUSE PANCREATIC ISLETS. Diabetes 2008; 57:1870-7. 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
  • 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
  • Lawler J, Detmar M. Tumor progression: the effects of thrombospondin-1 and -2. Int J Biochem Cell Biol 2004; 36:1038-45. 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
  • Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, Liau G. Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans. J Cell Biochem 2004; 91:766-76. 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
  • 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
  • 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
  • Lawler J, Miao WM, Duquette M, Bouck N, Bronson RT, Hynes RO. Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice. Am J Pathol 2001; 159:1949-56. PubMed
  • Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J. Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res 2001; 61:7830-9. PubMed
  • Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 2001; 98:12485-90. PubMed
  • Miao WM, Vasile E, Lane WS, Lawler J. CD36 associates with CD9 and integrins on human blood platelets. Blood 2001; 97:1689-96. PubMed
  • Streit M, Velasco P, Brown LF, Skobe M, Richard L, Riccardi L, Lawler J, Detmar M. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas. Am J Pathol 1999; 155:441-52. PubMed
  • Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998; 101:982-92. PubMed
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