title: Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation.
abstract: Tuberous sclerosis (TSC) is a tumor suppressor gene syndrome that is associated with the widespread development of mesenchymal tumor types. Genetically, TSC is said to occur through a classical biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induction of the mTOR pathway and subsequent tumorigenesis. High Mobility Group A2 (HMGA2), an architectural transcription factor, is known to regulate mesenchymal differentiation and drive mesenchymal tumorigenesis in vivo. Here, we investigated the role of HMGA2 in the pathogenesis of TSC using the TSC2(+/-) mouse model that similarly mirrors human disease and human tumor samples. We show that HMGA2 expression was detected in 100% of human and mouse TSC tumors and that HMGA2 activation was required for TSC mesenchymal tumorigenesis in genetically engineered mouse models. In contrast to the current dogma, the mTOR pathway was not activated in all TSC2(+/-) tumors and was elevated in only 50% of human mesenchymal tumors. Moreover, except for a subset of kidney tumors, tuberin was expressed in both human and mouse tumors. Therefore, haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated. Collectively, these findings demonstrate that tissue-specific genetic mechanisms are employed to promote tumor pathogenesis in TSC and identify a novel, critical pathway for potential therapeutic targeting.
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York. jmd12@cumc.columbia.edu.
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiomi
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marks
authors.affiliation: Center for Pulmonary Disease, Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.affiliation: Department of Biochemistry, Rutgers-Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey.
authors.forename: Devipriya
authors.initials: D
authors.lastname: Sankarasharma
authors.affiliation: Department of Biochemistry, Rutgers-Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey.
authors.forename: Kiran
authors.initials: K
authors.lastname: Chada
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D051379:Mice; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D025743:HMGA2 Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
references.citation: Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3
references.pmid: 5279523
references.citation: Am J Respir Crit Care Med. 2013 Mar 15;187(6):663-5
references.pmid: 23504366
references.citation: Science. 1990 Feb 23;247(4945):967-9
references.pmid: 2305264
references.citation: Cell. 1995 Jul 14;82(1):57-65
references.pmid: 7606786
references.citation: Cell. 2014 Feb 13;156(4):771-85
references.pmid: 24529379
references.citation: Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):55-61
references.pmid: 20123068
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9154-9
references.pmid: 8799170
references.citation: Genomics. 1994 Jul 1;22(1):68-76
references.pmid: 7959793
references.citation: Am J Pathol. 2005 Oct;167(4):1093-103
references.pmid: 16192644
references.citation: Nat Genet. 2010 May;42(5):454-8
references.pmid: 20400965
references.citation: Cancer Cell. 2006 Jun;9(6):459-71
references.pmid: 16766265
references.citation: Histopathology. 2002 May;40(5):458-63
references.pmid: 12010366
references.citation: Nature. 2006 May 25;441(7092):424-30
references.pmid: 16724053
references.citation: Mol Cancer Res. 2008 May;6(5):743-50
references.pmid: 18505920
references.citation: Oncogene. 2002 Dec 5;21(55):8470-6
references.pmid: 12466966
references.citation: Hum Mol Genet. 1998 Jun;7(6):1053-7
references.pmid: 9580671
references.citation: J Mol Cell Biol. 2011 Aug;3(4):206-20
references.pmid: 21138990
references.citation: Proc Am Thorac Soc. 2010 Feb;7(1):48-53
references.pmid: 20160148
references.citation: Genes Chromosomes Cancer. 2003 Dec;38(4):376-81
references.pmid: 14566858
references.citation: Cell. 2009 Oct 2;139(1):112-22
references.pmid: 19804757
references.citation: Ann N Y Acad Sci. 2010 Jan;1184:87-105
references.pmid: 20146692
references.citation: N Engl J Med. 2006 Sep 28;355(13):1345-56
references.pmid: 17005952
references.citation: Cancer Res. 2006 Aug 1;66(15):7453-9
references.pmid: 16885341
references.citation: Genes Chromosomes Cancer. 1996 Sep;17(1):1-6
references.pmid: 8889500
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3539-44
references.pmid: 18292222
references.citation: Mol Cell. 2008 Apr 25;30(2):214-26
references.pmid: 18439900
references.citation: Cancer Res. 2007 Mar 1;67(5):1902-9
references.pmid: 17332316
references.citation: Am J Pathol. 1996 Sep;149(3):775-9
references.pmid: 8780382
references.citation: Brain Pathol. 2010 Nov;20(6):1096-105
references.pmid: 20633017
references.citation: Mol Cell Biol. 2003 Dec;23(24):9104-16
references.pmid: 14645522
references.citation: Nucleic Acids Res. 2009 Jul;37(13):4371-84
references.pmid: 19465398
references.citation: Genes Dev. 2005 Aug 1;19(15):1779-86
references.pmid: 16027168
references.citation: Brain Pathol. 1999 Jan;9(1):45-54
references.pmid: 9989450
references.citation: BMC Pharmacol. 2009 Apr 15;9:8
references.pmid: 19368729
references.citation: J Transl Med. 2010 Feb 10;8:14
references.pmid: 20146790
references.citation: Am J Hum Genet. 1994 Aug;55(2):365-71
references.pmid: 8037213
references.citation: Mol Cell. 2003 Jun;11(6):1457-66
references.pmid: 12820960
references.citation: Genes Dev. 2009 Dec 1;23(23):2700-4
references.pmid: 19903759
references.citation: Genes Dev. 2008 Aug 15;22(16):2172-7
references.pmid: 18708577
references.citation: J Biol Chem. 2001 Aug 10;276(32):29805-14
references.pmid: 11390395
references.citation: Eur Respir J. 2006 May;27(5):1056-65
references.pmid: 16707400
references.citation: Am J Hum Genet. 1998 Apr;62(4):810-5
references.pmid: 9529362
references.citation: Am J Hum Genet. 1996 Aug;59(2):400-6
references.pmid: 8755927
references.citation: Lancet. 2008 Aug 23;372(9639):657-68
references.pmid: 18722871
references.citation: Cancer Res. 1999 Mar 15;59(6):1206-11
references.pmid: 10096549
references.citation: Eur J Hum Genet. 2005 Jun;13(6):731-41
references.pmid: 15798777
references.citation: Cancer Res. 2013 Jul 15;73(14):4289-99
references.pmid: 23722545
references.citation: Cell. 2005 Apr 22;121(2):179-93
references.pmid: 15851026
references.citation: Genes Chromosomes Cancer. 1998 Dec;23(4):350-7
references.pmid: 9824208
references.citation: N Engl J Med. 2011 Apr 28;364(17):1595-606
references.pmid: 21410393
references.citation: J Clin Invest. 2012 Nov;122(11):3807-16
references.pmid: 23114603
references.citation: Cell. 2009 May 29;137(5):873-86
references.pmid: 19446321
references.citation: Cancer Genet Cytogenet. 2010 Jan 15;196(2):119-23
references.pmid: 20082846
references.citation: Pediatr Nephrol. 2005 Jul;20(7):854-7
references.pmid: 15856327
references.citation: Nature. 1995 Aug 31;376(6543):771-4
references.pmid: 7651535
references.citation: J Clin Invest. 1999 Sep;104(6):687-95
references.pmid: 10491404
references.citation: Hum Mol Genet. 1994 Oct;3(10):1833-4
references.pmid: 7849709
references.citation: Science. 1997 Aug 8;277(5327):805-8
references.pmid: 9242607
references.citation: Mol Cancer Res. 2007 Apr;5(4):363-72
references.pmid: 17426251
references.citation: Cell Mol Life Sci. 2013 Aug;70(15):2657-75
references.pmid: 23069990