title: Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches.
abstract: Basal cell carcinoma (BCC) is characterized by frequent loss of PTCH1, leading to constitutive activation of the Hedgehog pathway. Although the requirement for Hedgehog in BCC is well established, the identity of disease-initiating cells and the compartments in which they reside remain controversial. By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC-like tumors. In contrast, stem cells within the interfollicular epidermis do not efficiently form tumors. Notably, we observed that innervated Gli1-expressing progenitors within mechanosensory touch dome epithelia are highly tumorigenic. Sensory nerves activate Hedgehog signaling in normal touch domes, while denervation attenuates touch dome-derived tumors. Together, our studies identify varying tumor susceptibilities among different stem cell populations in the skin, highlight touch dome epithelia as "hot spots" for tumor formation, and implicate cutaneous nerves as mediators of tumorigenesis.
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shelby C
authors.initials: SC
authors.lastname: Peterson
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Eberl
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Vagnozzi
authors.affiliation: Departments of Dermatology and Neuroscience, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Veniaminova
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Verhaegen
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bichakjian
authors.affiliation: Departments of Dermatology and Neuroscience, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: sunnyw@umich.edu.
authors.forename: Sunny Y
authors.initials: SY
authors.lastname: Wong
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002280:Basal Cell Carcinoma / Q000378:metabolism* / Q000473:pathology; D003714:Denervation; D004847:Epithelial Cells / Q000502:physiology*; D018859:Hair Follicle / Q000294:innervation / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008465:Mechanoreceptors / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000235:genetics; D018862:Merkel Cells / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009138:Musculocutaneous Nerve / Q000502:physiology* / Q000601:surgery; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D039904:Pluripotent Stem Cells / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; C514061:ihh protein, mouse
references.citation: Cell Rep. 2013 Jun 27;3(6):1759-65
references.pmid: 23727240
references.citation: Exp Cell Res. 2010 May 1;316(8):1422-8
references.pmid: 20338163
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8551-6
references.pmid: 10411913
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1434-9
references.pmid: 23292936
references.citation: Blood. 2007 Sep 15;110(6):1814-23
references.pmid: 17536012
references.citation: Nature. 2014 May 29;509(7502):617-21
references.pmid: 24717432
references.citation: Cell. 1996 Jun 14;85(6):841-51
references.pmid: 8681379
references.citation: J Cutan Pathol. 1999 Mar;26(3):113-8
references.pmid: 10235375
references.citation: Nat Rev Cancer. 2008 Oct;8(10):743-54
references.pmid: 18813320
references.citation: Development. 2010 Dec;137(23):3965-71
references.pmid: 21041368
references.citation: Cell. 2004 Aug 20;118(4):505-16
references.pmid: 15315762
references.citation: Genes Dev. 2004 Nov 15;18(22):2724-9
references.pmid: 15545630
references.citation: Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2273-9
references.pmid: 21933972
references.citation: Cell Stem Cell. 2009 Sep 4;5(3):267-78
references.pmid: 19664980
references.citation: Science. 1996 Jun 14;272(5268):1668-71
references.pmid: 8658145
references.citation: Nat Med. 1999 Nov;5(11):1285-91
references.pmid: 10545995
references.citation: Br J Dermatol. 2012 Jan;166(1):88-97
references.pmid: 21910710
references.citation: Dev Biol. 2003 Mar 15;255(2):238-48
references.pmid: 12648487
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4099-104
references.pmid: 21321199
references.citation: Science. 2013 Jul 12;341(6142):1236361
references.pmid: 23846904
references.citation: J Cell Biol. 2010 Oct 18;191(2):237-48
references.pmid: 20956378
references.citation: Genes Dev. 2000 Apr 15;14(8):994-1004
references.pmid: 10783170
references.citation: J Invest Dermatol. 2012 Jul;132(7):1927-30
references.pmid: 22418873
references.citation: Biochem Cell Biol. 1995 Sep-Oct;73(9-10):635-9
references.pmid: 8714683
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: Development. 2011 Feb;138(3):431-41
references.pmid: 21205788
references.citation: J Invest Dermatol. 1998 Jun;110(6):880-4
references.pmid: 9620293
references.citation: Genes Dev. 2009 Jan 1;23(1):24-36
references.pmid: 19136624
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3438-43
references.pmid: 10725363
references.citation: Am J Dermatopathol. 1997 Aug;19(4):341-50
references.pmid: 9261468
references.citation: Cancer Lett. 2003 Feb 10;190(1):45-50
references.pmid: 12536076
references.citation: J Cutan Pathol. 1997 Jan;24(1):14-24
references.pmid: 9027628
references.citation: Genes Dev. 2006 Feb 1;20(3):276-81
references.pmid: 16421275
references.citation: Cell. 2012 Mar 30;149(1):146-58
references.pmid: 22464327
references.citation: Development. 2013 Dec;140(24):4870-80
references.pmid: 24198274
references.citation: Nature. 1998 Jan 1;391(6662):90-2
references.pmid: 9422511
references.citation: J Invest Dermatol. 2014 Jul;134(7):1981-90
references.pmid: 24492243
references.citation: Oncogene. 1997 Aug 28;15(9):1059-67
references.pmid: 9285560
references.citation: Cancer Res. 2006 Oct 15;66(20):10171-8
references.pmid: 17047082
references.citation: Nat Cell Biol. 2010 Mar;12(3):299-305
references.pmid: 20154679
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4093-8
references.pmid: 21321207
references.citation: J Clin Invest. 2011 May;121(5):1681-3
references.pmid: 21519146
references.citation: Br J Dermatol. 1991 Dec;125(6):535-42
references.pmid: 1722110
references.citation: Eur J Cell Biol. 2005 Mar;84(2-3):259-71
references.pmid: 15819406
references.citation: J Clin Invest. 2011 Feb;121(2):613-22
references.pmid: 21206086
references.citation: J Clin Invest. 2011 May;121(5):1768-81
references.pmid: 21519145
references.citation: Science. 1997 May 2;276(5313):817-21
references.pmid: 9115210
references.citation: Cell Stem Cell. 2011 May 6;8(5):552-65
references.pmid: 21549329
references.citation: Cell Stem Cell. 2013 Oct 3;13(4):471-82
references.pmid: 23954751
references.citation: Anat Rec. 1983 Sep;207(1):79-88
references.pmid: 6638534
references.citation: Br J Dermatol. 2002 Jul;147(1):41-7
references.pmid: 12100183
references.citation: Oncogene. 2003 Aug 21;22(35):5415-26
references.pmid: 12934101
references.citation: J Invest Dermatol. 2011 Jul;131(7):1530-8
references.pmid: 21471984
references.citation: Hum Mol Genet. 1994 Mar;3(3):447-8
references.pmid: 8012356
references.citation: J Cutan Pathol. 2011 Jul;38(7):542-50
references.pmid: 21352265
references.citation: Neuroscience. 1984 Feb;11(2):521-33
references.pmid: 6717802
references.citation: Nat Genet. 2000 Mar;24(3):216-7
references.pmid: 10700170
references.citation: J Clin Invest. 2012 Feb;122(2):455-63
references.pmid: 22293184
references.citation: Science. 2009 Jun 19;324(5934):1580-2
references.pmid: 19541997
references.citation: Cancer Cell. 2011 Jan 18;19(1):114-24
references.pmid: 21215705
references.citation: J Invest Dermatol. 1993 Jan;100(1):69-76
references.pmid: 7678634
references.citation: J Skin Cancer. 2012;2012:907543
references.pmid: 23024864