Photo of Michael Klagsbrun,  PhD

Michael Klagsbrun, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2157


michael.klagsbrun@childrens.harvard.edu

Michael Klagsbrun, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Patricia A. Donahoe Professor of Surgery (Pathology), Surgery, Harvard Medical School
  • Principal Investigator, Surgery, Vascular Biology Program, Boston Children's Hospital

Research Abstract

My laboratory's research is focused primarily on vascular growth factors and their receptors. In particular, we study growth factor/receptor-mediated mechanisms associated with angiogenesis. Knowledge of these mechanisms is used to develop angiogenesis inhibitors. VEGF is a major regulator of angiogenesis. We recently identified neuropilin-1 (NRP1) as a VEGF receptor that is expressed by endothelial cells (EC) and tumor cells. NRP is also a receptor for semaphorins, chemorepulsants that repel axons and collapse growth cones. We have found that semaphorins are inhibitors of EC motility, suggesting a possible molecular connection in the mechanisms that regulate neuronal and capillary migration. Recently, we cloned a soluble form of NRP1 (sNRP1). sNRP1 is a VEGF antagonist, and its expression in tumor cells results in decreased vascularity and increased tumor necrosis. Together, these results suggest that antagonists of NRP1 are potential antagonists of angiogenesis and tumor progression.

Publications

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  • Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, Moses MA, Klagsbrun M, Bischoff J, Graier WF. The GPR 55 agonist, L-留-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol 2015. PubMed
  • Boscolo E, Coma S, Luks VL, Greene AK, Klagsbrun M, Warman ML, Bischoff J. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis 2015; 18:151-62. PubMed
  • Huang L, Nakayama H, Klagsbrun M, Mulliken JB, Bischoff J. Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 2014. PubMed
  • Panigrahy D, Adini I, Mamluk R, Levonyak N, Bruns CJ, D'Amore PA, Klagsbrun M, Bielenberg DR. Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology 2014; 46:416-23. PubMed
  • Akino T, Han X, Nakayama H, McNeish BL, Zurakowski D, Mammoto A, Klagsbrun M, Smith E. Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of pediatric medulloblastoma patients. Cancer Res 2014. PubMed
  • Procaccia V, Nakayama H, Shimizu A, Klagsbrun M. Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. Biochem Biophys Res Commun 2014. PubMed
  • Coma S, Allard-Ratick M, Akino T, van Meeteren LA, Mammoto A, Klagsbrun M. GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. Angiogenesis 2013; 16:939-52. PubMed
  • Shimizu A, Nakayama H, Wang P, König C, Akino T, Sandlund J, Coma S, Italiano JE, Mammoto A, Bielenberg DR, Klagsbrun M. Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem 2013; 288:2210-22. PubMed
  • Dudley AC, Udagawa T, Melero-Martin JM, Shih SC, Curatolo A, Moses MA, Klagsbrun M. Bone marrow is a reservoir for pro-angiogenic myelomonocytic cells but not endothelial cells in spontaneous tumors. Blood 2010; 116:3367-71. PubMed
  • Klagsbrun M, Shimizu A. Semaphorin 3E, an exception to the rule. J Clin Invest 2010; 120:2658-60. PubMed
  • Geretti E, van Meeteren LA, Shimizu A, Dudley AC, Claesson-Welsh L, Klagsbrun M. A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol Cancer Res 2010; 8:1063-73. PubMed
  • Coma S, Amin DN, Shimizu A, Lasorella A, Iavarone A, Klagsbrun M. Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res 2010; 70:3823-32. PubMed
  • Dudley AC, Klagsbrun M. Tumor endothelial cells join the resistance. Clin Cancer Res 2009; 15:4787-9. PubMed
  • Dudley AC,Klagsbrun M. Tumor endothelial cells have features of adult stem cells. Cell Cycle 2009; 8:236-8. PubMed
  • Dudley AC,Khan ZA,Shih SC,Kang SY,Zwaans BM,Bischoff J,Klagsbrun M. Calcification of multipotent prostate tumor endothelium. Cancer Cell 2008; 14:201-11. PubMed
  • Amin DN, Bielenberg DR, Lifshits E, Heymach JV, Klagsbrun M. Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc Res 2008; 76:15-22. PubMed
  • Geretti E, Shimizu A, Klagsbrun M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 2008; 11:31-39. PubMed
  • Bielenberg DR, Klagsbrun M. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev 2007; 26:421-31. PubMed
  • Geretti E, Shimizu A, Kurschat P, Klagsbrun M. Site-directed mutagenesis in the B-neuropilin-2 domain selectively enhances its affinity to VEGF165, but not to semaphorin 3F. J Biol Chem 2007; 282:25698-707. PubMed
  • Klagsbrun M, Eichmann A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev 2005; 16:535-48. PubMed
  • Hida K, Klagsbrun M. A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res 2005; 65:2507-10. PubMed
  • Nishi E, Klagsbrun M. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a mediator of multiple physiological and pathological pathways. Growth Factors 2004; 22:253-60. PubMed
  • Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 2004; 64:8249-55. PubMed
  • Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 2004; 114:1260-71. PubMed
  • Bovenkamp DE, Goishi K, Bahary N, Davidson AJ, Zhou Y, Becker T, Becker CG, Zon LI, Klagsbrun M. Expression and mapping of duplicate neuropilin-1 and neuropilin-2 genes in developing zebrafish. Gene Expr Patterns 2004; 4:361-70. PubMed
  • Goishi K, Klagsbrun M. Vascular endothelial growth factor and its receptors in embryonic zebrafish blood vessel development. Curr Top Dev Biol 2004; 62:127-52. PubMed
  • Goishi K, Lee P, Davidson AJ, Nishi E, Zon LI, Klagsbrun M. Inhibition of zebrafish epidermal growth factor receptor activity results in cardiovascular defects. Mech Dev 2003; 120:811-22. PubMed
  • Coma S, Shimizu A, Klagsbrun M. Hypoxia induces tumor and endothelial cell migration in a semaphorin 3F- and VEGF-dependent manner via transcriptional repression of their common receptor neuropilin 2. Cell Adh Migr 2011; 5:266-75. PubMed
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