1. Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice.
- Author
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Brandes N, Mitkovska SH, Botermann DS, Maurer W, Müllen A, Scheile H, Zabel S, Frommhold A, Heß I, Hahn H, and Uhmann A
- Subjects
- Age Factors, Animals, Carcinoma, Basal Cell metabolism, Disease Susceptibility, Epidermal Cells metabolism, Epidermal Cells pathology, Fluorescent Antibody Technique, Gene Knock-In Techniques, Genes, Reporter, Hair Follicle metabolism, Hair Follicle pathology, Humans, Immunohistochemistry, Immunophenotyping, Mice, Mice, Transgenic, Patched-1 Receptor metabolism, Skin metabolism, Skin pathology, Skin Neoplasms genetics, Skin Neoplasms metabolism, Stem Cells metabolism, Stem Cells pathology, Carcinoma, Basal Cell genetics, Carcinoma, Basal Cell pathology, Cell Transformation, Neoplastic genetics, Mutation, Patched-1 Receptor genetics
- Abstract
Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre -mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre -targeted BCC progenitors as rare Keratin 5
+ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5+ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.- Published
- 2020
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