Jack Lawler, Ph.D.
Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-270K
Boston, MA 02215
Jack Lawler received his Ph.D. in Physics from Boston College in 1976, and performed postdoctoral training at the Dana Farber Cancer Center. Over the past 30 years, Dr. Lawler’s laboratory has utilized a wide range of technologies to elucidate the structure and function of the thrombospondins. He has authored over 170 publications and has co-authored the book “The Thrombospondin Gene Family”. In 1996, Dr. Lawler joined the Department of Pathology at the Beth Israel Deaconess Medical Center where he is currently the Director of the Division of Cancer Biology and Angiogenesis and Professor of Pathology at Harvard Medical School.
Research Interests: The Regulation of Tissue Remodeling & Angiogenesis by Thrombospondins (Tissue Remodeling & Angiogenesis by Thrombospondins)
Basic Research - The thrombospondins (TSPs) are a family of five extracellular, calcium-binding proteins that are important for the tissue remodeling that occurs during development, synaptogenesis, wound healing, angiogenesis and neoplasia. In addition, cartilage oligomeric matrix protein (COMP), also known as TSP-5, is a key regulator of the structure and function of cartilage. TSPs regulate extracellular matrix structure through interactions with matrix proteins and proteases. At the cell surface, TSP-1 affects migration, proliferation and survival through interactions with proteoglycans, integrins, and CD36. The goal of our research is to obtain a detailed comprehension of the structure and function of the members of the TSP gene family. We use X-ray crystallography to determine the structure of the various domains of these proteins, either alone or as complexes with their ligands. TSP-1 and -2 are potent endogenous inhibitors of angiogenesis and tumor progression. Ongoing experiments indicate that specific structures within the type 1 repeats (TSRs) of TSP-1 and -2 mediate these activities. The membrane protein CD36 mediates the effects of the TSRs on endothelial cell migration and apoptosis. We are currently working to identify signaling molecules and other membrane proteins that collaborate with CD36 to inhibit endothelial cell function. These studies may identify novel targets for the inhibition of angiogenesis and tumor growth.
Translational Research - We have found that a recombinant version of all three type 1 repeats of TSP-1, designated 3TSR, inhibits tumor growth in murine models of pancreatic, breast, colon, skin and ovarian cancer. This inhibition is associated with a greater than three-fold increase in tumoral endothelial cell apoptosis. We have recently found that 3TSR is particularly active in an orthotopic syngeneic model of epithelial ovarian cancer (EOC). When 3TSR is used as a single agent and treatment is initiated at advanced stages of disease in an intervention trial, mice show tumor regression and greatly increased survival. Further increases in survival are seen when 3TSR is combined with chemotherapy. Knockdown of the membrane protein CD36 inhibits the ability of 3TSR to induce apoptosis of both endothelial and EOC cells. Thus, the TSP-1/CD36 axis in EOC represents a unique opportunity to concomitantly target two cell populations that are key to cancer progression, tumor and endothelial cells, with a single reagent (Fig. 1). Since 3TSR decreases VEGF expression, it is able to simultaneously suppress survival and induce apoptosis in both cell types. We have also shown that 3TSR inhibits VEGF-induced vascular permeability. This activity may suppress ascites formation and markedly improve the overall health of the patients.
Epithelial ovarian cancer is the most common malignancy of the female reproductive tract with about 220,000 new cases diagnosed each year worldwide. Because it is detected late in progression in 80% of the cases, over 140,000 of these women die each year from EOC. The five-year survival rate for ovarian cancer patients has changed very little over the last 20 years and new treatment approaches are urgently needed. Our preclinical research represents important steps toward developing a new therapeutic option for the treatment of ovarian cancer, and we anticipate that the results of these studies will pave the way for human clinical trials.
New and Noteworthy Publications:
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; 117(17): 4658-66. We found that a portion of vascular endothelial cell growth factor receptor-2 (VEGFR-2) and CD36 associate with integrins within tetraspanin-enriched microdomains. Thrombospondin-1 promotes the association of VEGFR-2 with this complex and facilitates crosstalk between pro- and anti-angiogenic signal transduction pathways.
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(23): 10649-54. The oncogenic V600E mutation in B-Raf promotes the expression of extracellular matrix molecules, including thrombospondin-1. We hypothesize that these matrix molecules promote invasion of thyroid cancer cells harboring B-Raf(V600E).
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 Oct;23(10): 3368-76. This study shows that some CD36 molecules are in close proximity to VEGFR-2 and integrins in the endothelial cell membrane. We show that a recombinant version of the three type 1 repeats, designated 3TSR, inhibits the phosphorylation of VEGFR-2 in response to VEGF. These data indicate that 3TSR inhibits angiogenesis by suppressing pro-survival pathways through VEGFR-2 while inducing apoptosis through CD36.
Tan K, Duquette M, Liu J-h, Dong Y, Zhang R, Joachimiak A, Lawler J, Wang J-h. Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implications. J. Cell Biol. 2002. 159: 373-382. Drs. Wang and Lawler are corresponding authors. To better understand the molecular basis for the inhibition of angiogenesis by TSP-1, we determined the structure of the TSRs by X-ray crystallography. The TSRs represent a novel β-strand fold that is stabilized by cation- interactions between arginine and tryptophan residues.
Lawler J, Hynes RO. The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol. 1986; 103:1635-1648. This is the first report of the cloning and sequencing of a member of the thrombospondin gene family. A novel amino acid sequence repeat that is present in many genes (the TSR) and the structural basis for high capacity calcium binding were identified in this study.