Photo of Martin E. Hemler,  PhD

Martin E. Hemler, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3410
Fax: (617) 632-2662


martin_hemler@dfci.harvard.edu

Martin E. Hemler, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Pathology, Harvard Medical School
  • Professor, Cancer Immunology and Virology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory focuses on novel molecules and pathways that control tumor growth, metastasis and drug resistance. We study a tetraspanin protein, called CD151, that associates with laminin-binding integrins and regulates their contributions to tumor initiation, promotion, progression, invasion and metastasis. Also we have gained new molecular insights into how a novel subpopulation of CD151 supports resistance to many anti-cancer drugs. Also, we have uncovered novel positive and negative regulators of TGF-β signaling. We learned that tetraspanin proteins CD9 and CD81 make vital contributions towards TGF-β1 receptor assembly and signaling. Conversely, the EWI-2 protein associates tightly with CD9 and CD81, thus inhibiting TGF-β1 signaling. These findings have wide implications and provide novel insights into dual roles of TGF-β1 as it inhibits primary tumor growth, but supports EMT, invasion and metastasis. Additionally, we noted that assembly of protein complexes, called tetraspanin-enriched microdomains (TEMS) is facilitated by palmitoylation of tetraspanins, integrins, and other proteins found within TEMS. We learned that palmitoylation of tetraspanin proteins is largely mediated by a palmitoyl acyl transferase called DHHC2, whereas palmitoylation of integrin α6 and β4 subunits is mediated by DHHC3. In further studies of DHHC3, we found that it is a major contributor to tumor growth in vivo, by a mechanism that involves negative regulation of oxidative stress and senescence in tumor cells.

Publications

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  • Wang HX, Sharma C, Knoblich K, Granter SR, Hemler ME. EWI-2 negatively regulates TGF-β signaling leading to altered melanoma growth and metastasis. Cell Res 2015; 25:370-85. PubMed
  • Knoblich K, Wang HX, Sharma C, Fletcher AL, Turley SJ, Hemler ME. Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation. Cell Mol Life Sci 2014; 71:1305-14. PubMed
  • Hemler ME. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer 2014; 14:49-60. PubMed
  • Deng X, Li Q, Hoff J, Novak M, Yang H, Jin H, Erfani SF, Sharma C, Zhou P, Rabinovitz I, Sonnenberg A, Yi Y, Zhou P, Stipp CS, Kaetzel DM, Hemler ME, Yang XH. Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis. Neoplasia 2012; 14:678-89. PubMed
  • Tsujino K, Takeda Y, Arai T, Shintani Y, Inagaki R, Saiga H, Iwasaki T, Tetsumoto S, Jin Y, Ihara S, Minami T, Suzuki M, Nagatomo I, Inoue K, Kida H, Kijima T, Ito M, Kitaichi M, Inoue Y, Tachibana I, Takeda K, Okumura M, Hemler ME, Kumanogoh A. Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity. Am J Respir Crit Care Med 2012; 186:170-80. PubMed
  • Sharma C, Rabinovitz I, Hemler ME. Palmitoylation by DHHC3 is critical for the function, expression, and stability of integrin α6β4. Cell Mol Life Sci 2012. PubMed
  • Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P, Gonzalez SF, Elpek KG, Chang SK, Knoblich K, Hemler ME, Brenner MB, Carroll MC, Mooney DJ, Turley SJ, . Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol 2012; 13:499-510. PubMed
  • Yang XH, Mirchev R, Deng X, Yacono P, Yang HL, Golan DE, Hemler ME. CD151 restricts the α6 integrin diffusion mode. J Cell Sci 2012. PubMed
  • Wang HX, Kolesnikova TV, Denison C, Gygi SP, Hemler ME. The C-terminal tail of tetraspanin protein CD9 contributes to its function and molecular organization. J Cell Sci 2011; 124:2702-10. PubMed
  • Takeda Y, Li Q, Kazarov AR, Epardaud M, Elpek K, Turley SJ, Hemler ME. Diminished metastasis in tetraspanin CD151-knockout mice. Blood 2011; 118:464-72. PubMed
  • Wang HX, Li Q, Sharma C, Knoblich K, Hemler ME. Tetraspanin protein contributions to cancer. Biochem Soc Trans 2011; 39:547-52. PubMed
  • Yang XH, Flores LM, Li Q, Zhou P, Xu F, Krop IE, Hemler ME. Disruption of Laminin-Integrin-CD151-Focal Adhesion Kinase Axis Sensitizes Breast Cancer Cells to ErbB2 Antagonists. Cancer Res 2010; 70:2256-63. PubMed
  • Xu D, Sharma C, Hemler ME. Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J 2009; 23:3674-81. PubMed
  • Lafleur MA,Xu D,Hemler ME. Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis. Mol Biol Cell 2009; 20:2030-40. PubMed
  • Kolesnikova TV,Kazarov AR,Lemieux ME,Lafleur MA,Kesari S,Kung AL,Hemler ME. Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo. Neoplasia 2008; 11:77-86, 4p following 86. PubMed
  • Fiorentino M,Zadra G,Palescandolo E,Fedele G,Bailey D,Fiore C,Nguyen PL,Migita T,Zamponi R,Di Vizio D,Priolo C,Sharma C,Xie W,Hemler ME,Mucci L,Giovannucci E,Finn S,Loda M. Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer. Lab Invest 2008; 88:1340-8. PubMed
  • Hemler ME. Targeting of tetraspanin proteins--potential benefits and strategies. Nat Rev Drug Discov 2008; 7:747-58. PubMed
  • Sharma C,Yang XH,Hemler ME. DHHC2 affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151. Mol Biol Cell 2008; 19:3415-25. PubMed
  • Yang XH, Richardson AL, Torres-Arzayus MI, Zhou P, Sharma C, Kazarov AR, Andzelm MM, Strominger JL, Brown M, Hemler ME. CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization. Cancer Res 2008; 68:3204-13. PubMed
  • Kovalenko OV, Yang XH, Hemler ME. A novel cysteine cross-linking method reveals a direct association between claudin-1 and tetraspanin CD9. Mol Cell Proteomics 2007; 6:1855-67. PubMed
  • Takeda Y, Kazarov AR, Butterfield CE, Hopkins BD, Benjamin LE, Kaipainen A, Hemler ME. Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 2006; 109:1524-32. PubMed
  • Wunschmann S, Muller HM, Stipp CS, Hemler ME, Stapleton JT. In vitro interaction between hepatitis C virus (HCV) envelope glycoprotein E2 and serum lipoproteins (LPs) results in enhanced cellular binding of both HCV E2 and LPs. J Infect Dis 2006; 194:1058-67. PubMed
  • Sala-Valdés M, Ursa A, Charrin S, Rubinstein E, Hemler ME, Sánchez-Madrid F, Yáñez-Mó M. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins. J Biol Chem 2006; 281:19665-75. PubMed
  • Yang XH, Kovalenko OV, Kolesnikova TV, Andzelm MM, Rubinstein E, Strominger JL, Hemler ME. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. J Biol Chem 2006; 281:12976-85. PubMed
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