title: Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations.
abstract: Uncontrolled Hedgehog (Hh) signaling leads to the development of basal cell carcinoma (BCC), the most common human cancer, but the cell of origin for BCC is unclear. While Hh pathway dysregulation is common to essentially all BCCs, there exist multiple histological subtypes, including superficial and nodular variants, raising the possibility that morphologically distinct BCCs may arise from different cellular compartments in skin. Here we have shown that induction of a major mediator of Hh signaling, GLI2 activator (GLI2ΔN), selectively in stem cells of resting hair follicles in mice, induced nodular BCC development from a small subset of cells in the lower bulge and secondary hair germ compartments. Tumorigenesis was markedly accelerated when GLI2ΔN was induced in growing hair follicles. In contrast, induction of GLI2ΔN in epidermis led to the formation of superficial BCCs. Expression of GLI2ΔN at reduced levels in mice yielded lesions resembling basaloid follicular hamartomas, which have previously been linked to low-level Hh signaling in both mice and humans. Our data show that the cell of origin, tissue context (quiescent versus growing hair follicles), and level of oncogenic signaling can determine the phenotype of Hh/Gli-driven skin tumors, with high-level signaling required for development of superficial BCC-like tumors from interfollicular epidermis and nodular BCC-like tumors from hair follicle stem cells.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Grachtchouk
authors.forename: Joanna
authors.initials: J
authors.lastname: Pero
authors.forename: Steven H
authors.initials: SH
authors.lastname: Yang
authors.forename: Alexandre N
authors.initials: AN
authors.lastname: Ermilov
authors.forename: L Evan
authors.initials: LE
authors.lastname: Michael
authors.forename: Aiqin
authors.initials: A
authors.lastname: Wang
authors.forename: Dawn
authors.initials: D
authors.lastname: Wilbert
authors.forename: Rajiv M
authors.initials: RM
authors.lastname: Patel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferris
authors.forename: James
authors.initials: J
authors.lastname: Diener
authors.forename: Mary
authors.initials: M
authors.lastname: Allen
authors.forename: Seokchun
authors.initials: S
authors.lastname: Lim
authors.forename: Li-Jyun
authors.initials: LJ
authors.lastname: Syu
authors.forename: Monique
authors.initials: M
authors.lastname: Verhaegen
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
mesh_terms: D000483:Alleles; D000818:Animals; D002280:Basal Cell Carcinoma / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D018859:Hair Follicle / Q000378:metabolism*; D006222:Hamartoma / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000075746:Zinc Finger Protein Gli2