Photo of Elizabeth Henske,  MD

Elizabeth Henske, MD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 355-9049
Fax: (617) 355-9016


ehenske@partners.org

Elizabeth Henske, MD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The primary focus of my laboratory is the pathogenesis of tuberous sclerosis complex (TSC) and the related disorder, lymphangioleiomyomatosis (LAM). TSC is a multisystem disorder in which the manifestations can include tumors in the brain, heart, kidney, and skin, as well as mental retardation and autism. My laboratory has a particular interest in the renal manifestations of TSC (cysts, angiomyolipomas, and carcinomas) and in the pulmonary manifestation, LAM. About 30% of women with TSC develop LAM, which is an unusual lung disease in which benign-appearing smooth muscle cells proliferate extensively in the lungs, leading to cystic, emphysema-like lung destruction and lung failure. LAM pathogenesis appears to involve one of the most unusual pathogenic mechanisms in human disease: the metastasis of histologically benign cells.

The protein products of the TSC1 and TSC2 genes (hamartin and tuberin, respectively) physically interact to inhibit the activity of the kinase, TORC1. This mTOR inhibition is achieved the small GTPase Rheb which is regulated by the GAP (GTPase activating protein) region of TSC2. A great deal of attention has been focused on the role of TORC1, which is inhibited by Rapamycin, in the pathogenesis of TSC and LAM. A key area of uncertainty is whether Rheb has TORC1-independent targets that are disease-relevant.

Currently the laboratory is examining 1) the mechanisms through which estrogen may promote the metastasis of TSC2-null cells, thereby promoting LAM pathogenesis, 2) the role of the TSC pathway in neural development, using a Drosophila model, and 3) the connections between the TSC proteins and the Birt-Hogg-Dube (BHD) protein. BHD (like TSC) is associated with renal cell carcinoma and cystic lung disease. In S. Pombe we have found that the BHD homolog functions in the TOR signaling pathway, but in opposition to the TSC proteins.

Publications

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  • El-Chemaly S, Henske EP. The next breakthrough in LAM clinical trials may be their design: challenges in design and execution of future LAM clinical trials. Expert Rev Respir Med 2015; 9:195-204. PubMed
  • Priolo C, Ricoult SJ, Khabibullin D, Filippakis H, Yu J, Manning BD, Clish C, Henske EP. TSC2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2015. PubMed
  • El-Chemaly S, Henske EP. Towards personalised therapy for lymphangioleiomyomatosis: lessons from cancer. Eur Respir Rev 2014; 23:30-5. PubMed
  • Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, Mizumura K, Xu W, Malinowska IA, Yu J, Kwiatkowski DJ, Locasale JW, Asara JM, Choi AM, Finkel T, Henske EP. Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res 2014; 12:48-57. PubMed
  • Ma N, Liu Q, Zhang L, Henske EP, Ma Y. TORC1 signaling is governed by two negative regulators in fission yeast. Genetics 2013; 195:457-68. PubMed
  • Gu X, Yu JJ, Ilter D, Blenis N, Henske EP, Blenis J. Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. Proc Natl Acad Sci U S A 2013; 110:14960-5. PubMed
  • Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013; 153:840-54. PubMed
  • Priolo C, Henske EP. Metabolic reprogramming in polycystic kidney disease. Nat Med 2013; 19:407-9. PubMed
  • Li C, Zhou X, Sun Y, Zhang E, Mancini JD, Parkhitko A, Morrison TA, Silverman EK, Henske EP, Yu JJ. Faslodex Inhibits Estradiol-induced ECM Dynamics and Lung Metastasis in a Model of LAM. Am J Respir Cell Mol Biol 2013. PubMed
  • Trindade AJ, Medvetz DA, Neuman NA, Myachina F, Yu J, Priolo C, Henske EP. MicroRNA-21 is induced by rapamycin in a model of tuberous sclerosis (TSC) and lymphangioleiomyomatosis (LAM). PLoS ONE 2013; 8:e60014. PubMed
  • McCormack FX, Travis WD, Colby TV, Henske EP, Moss J. Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med 2012; 186:1210-2. PubMed
  • Henske EP, McCormack FX. Lymphangioleiomyomatosis - a wolf in sheep's clothing. J Clin Invest 2012; 122:3807-16. PubMed
  • Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP. Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS ONE 2012; 7:e47842. PubMed
  • Liu F, Lunsford EP, Tong J, Ashitate Y, Gibbs SL, Yu J, Choi HS, Henske EP, Frangioni JV. Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex. PLoS ONE 2012; 7:e38589. PubMed
  • Neuman NA, Henske EP. Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis. EMBO Mol Med 2011; 3:189-200. PubMed
  • Nurok M, Eslick I, Carvalho CR, Costabel U, D'Armiento J, Glanville AR, Harari S, Henske EP, Inoue Y, Johnson SR, Lacronique J, Lazor R, Moss J, Ruoss SJ, Ryu JH, Seyama K, Watz H, Xu KF, Hohmann EL, Moss F. The International LAM Registry: A Component of an Innovative Web-Based Clinician, Researcher, and Patient-Driven Rare Disease Research Platform. Lymphat Res Biol 2010; 8:81-7. PubMed
  • Yu J, Henske EP. mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The "Perfect Storm" of Pro-Metastatic Factors in LAM Pathogenesis. Lymphat Res Biol 2010; 8:43-9. PubMed
  • Yu J, Parkhitko AA, Henske EP. Mammalian target of rapamycin signaling and autophagy: roles in lymphangioleiomyomatosis therapy. Proc Am Thorac Soc 2010; 7:48-53. PubMed
  • Karbowniczek M, Zitserman D, Khabibullin D, Hartman T, Yu J, Morrison T, Nicolas E, Squillace R, Roegiers F, Henske EP. The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. J Clin Invest 2010; 120:93-102. PubMed
  • Matthew EM, Hart LS, Astrinidis A, Navaraj A, Dolloff NG, Dicker DT, Henske EP, El-Deiry WS. The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle 2009; 8:4168-75. PubMed
  • Yu JJ,Robb VA,Morrison TA,Ariazi EA,Karbowniczek M,Astrinidis A,Wang C,Hernandez-Cuebas L,Seeholzer LF,Nicolas E,Hensley H,Jordan VC,Walker CL,Henske EP. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci U S A 2009; 106:2635-40. PubMed
  • Hartman TR,Liu D,Zilfou JT,Robb V,Morrison T,Watnick T,Henske EP. The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol Genet 2008; 18:151-63. PubMed
  • Karbowniczek M,Spittle CS,Morrison T,Wu H,Henske EP. mTOR is activated in the majority of malignant melanomas. J Invest Dermatol 2007; 128:980-7. PubMed
  • Lee CH,Inoki K,Karbowniczek M,Petroulakis E,Sonenberg N,Henske EP,Guan KL. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 2007; 26:4812-23. PubMed
  • Pugacheva EN,Jablonski SA,Hartman TR,Henske EP,Golemis EA. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 2007; 129:1351-63. PubMed
  • Kayyali US, Larsen CG, Bashiruddin S, Lewandowski SL, Trivedi CM, Warburton RR, Parkhitko AA, Morrison TA, Henske EP, Chekaluk Y, Kwiatkowski DJ, Finlay GA. Targeted deletion of Tsc1 causes fatal cardiomyocyte hyperplasia independently of afterload. Cardiovasc Pathol 2015; 24:80-93. PubMed
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