This week we would like to introduce you to the work of Professor Elizabeth Henske, Founding Director of the Centre for LAM Research and Clinical Care at Brigham and Women’s Hospital, Boston, MA. Dr Henske is also a Professor of Medicine at Harvard Medical School; an Associate Member of the BROAD Institute of MIT and Harvard; a member of the Board of Directors of the TS Alliance; and a practicing medical oncologist at the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute. Professor Henske and her team focus on how genetic mutations cause Tuberous sclerosis complex (TSC), Lymphangioleiomyomatosis (LAM) and Birt-Hogg-Dubé Syndrome (BHD).
TSC is caused by mutations in the TSC1 or TSC2 genes, and is characterised by the growth of benign tumours in the brain, eyes, heart, kidney, skin and lungs. LAM, a cystic lung disease characterised by aberrant proliferation of smooth muscle cells in the lungs, and is also a symptom of TSC. 30% of female TSC patients develop LAM compared with 10% of male patients. LAM can also occur sporadically, almost exclusively in women from about the age of 30.
Professor Henske has concentrated on TSC for much of her career, having been part of the team that cloned the TSC1 gene in 1995 (Nahmias et al., 1995). In 2000, her team discovered that sporadic LAM is caused by somatic mutations in the TSC2 gene (Carsillo et al., 2000), and in 2009 the team found that TSC2-/- cells metastasise to the lungs, causing LAM symptoms to develop in mice (Yu et al., 2009). Furthermore, the metastatic potential of these histologically benign cells was increased when male and female mice were treated with estrogen, which may explain the female predominance of LAM patients. Investigating the mechanisms that underlie the female predominance of LAM remains a major focus of Professor Henske’s laboratory.
More recently, Professor Henske’s team reported that combined inhibition of mTOR signalling and autophagy with Rapamycin and Chloroquine inhibited the growth of TSC2-/- xenografts tumours, and the development of spontaneous renal tumours in TSC2+/- mice (Parkhitko et al., 2011). This study formed the basis of the SAIL trial, which is currently enrolling and will test the efficacy of this combined therapy for LAM.
Professor Henske’s research interests also include how FLCN mutations cause the symptoms seen in BHD syndrome. Professor Henske originally became interested in BHD syndrome due to the overlap in clinical symptoms with TSC, namely the development of benign skin tumours, kidney tumours and lung cysts. Her team generated the first yeast and heterozygous mouse models of BHD (Hartman et al., 2009; van Slegtenhorst et al., 2007). Both studies gave early indications that FLCN loss leads to dysregulated mTOR signalling, implying that there is a shared underlying mechanism in the pathogenesis of BHD, TSC and LAM. Last year, Professor Henske’s team found that FLCN interacts with PKP4, through which it regulates RhoA signalling, cell migration and cell-cell adhesion (Medvetz et al., 2012), further suggesting shared disease mechanisms between BHD and TSC, as Professor Henske’s team had previously shown that TSC2 also regulates these processes (Astrinidis et al., 2002).
To find out more about Professor Henske and her work, please watch our video interview (with its accompanying transcript and audio-only files). A video interview with Dr Douglas Medvetz, the Postdoctoral Research Fellow in Professor Henske’s lab leading the BHD work, is also available.
- Astrinidis A, Cash TP, Hunter DS, Walker CL, Chernoff J, & Henske EP (2002). Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene, 21 (55), 8470-6 PMID: 12466966
- Carsillo T, Astrinidis A, & Henske EP (2000). Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proceedings of the National Academy of Sciences of the United States of America, 97 (11), 6085-90 PMID: 10823953
- Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, & Henske EP (2009). The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene, 28 (13), 1594-604 PMID: 19234517
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). 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, 7 (11) PMID: 23139756
- Nahmias J, Hornigold N, Fitzgibbon J, Woodward K, Pilz A, Griffin D, Henske EP, Nakamura Y, Graw S, & Florian F (1995). Cosmid contigs spanning 9q34 including the candidate region for TSC1. European journal of human genetics : EJHG, 3 (2), 65-77 PMID: 7552144
- Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, & Henske EP (2011). Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108 (30), 12455-60 PMID: 21746920
- van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, & Henske EP (2007). The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. The Journal of biological chemistry, 282 (34), 24583-90 PMID: 17556368
- 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 (2009). Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proceedings of the National Academy of Sciences of the United States of America, 106 (8), 2635-40 PMID: 19202070