Identification of the cell lineage at the origin of basal cell carcinoma.
For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated Hedgehog signalling in different cellular compartments of the skin epidermis and determined in which compartments Hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC does not originate from bulge stem cells, as previously thought. Using clonal analysis, we found that BCC arises from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessarily predictive of the cancer initiating cells.
Youssef
Khalil Kass
KK
Université Libre de Bruxelles (ULB), IRIBHM, Brussels B-1070, Belgium.
Van Keymeulen
Alexandra
A
Lapouge
Gäelle
G
Beck
Benjamin
B
Michaux
Cindy
C
Achouri
Younes
Y
Sotiropoulou
Panagiota A
PA
Blanpain
Cédric
C
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002454:Cell Differentiation; D019070:Cell Lineage; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004431:Ear, External / Q000473:pathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017930:Genes, Reporter / Q000235:genetics; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D039663:Integrin beta4 / Q000378:metabolism; D053550:Keratin-10 / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics; D053569:Keratin-15 / Q000235:genetics / Q000378:metabolism; D053539:Keratin-19 / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D000072086:Smoothened Receptor; D013623:Tail / Q000473:pathology
D001426:Bacterial Proteins; D015820:Cadherins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D053823:Hedgehog Proteins; D039663:Integrin beta4; D053547:Keratin-14; D053569:Keratin-15; D053539:Keratin-19; C507491:Krt10 protein, mouse; C507446:Krt14 protein, mouse; C492053:Krt15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D000072079:Patched Receptors; D011506:Proteins; D022661:RNA, Untranslated; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C054562:yellow fluorescent protein, Bacteria; D053550:Keratin-10; C045073:Cre recombinase; D019426:Integrases