Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment.
Notch1 is a proto-oncogene in several organs. In the skin, however, Notch1 deletion leads to tumor formation, suggesting that Notch1 is a "tumor suppressor" within this context. Here we demonstrate that, unlike classical tumor suppressors, Notch1 loss in epidermal keratinocytes promotes tumorigenesis non-cell autonomously by impairing skin-barrier integrity and creating a wound-like microenvironment in the skin. Using mice with a chimeric pattern of Notch1 deletion, we determined that Notch1-expressing keratinocytes in this microenvironment readily formed papillomas, showing that Notch1 was insufficient to suppress this tumor-promoting effect. Accordingly, loss of other Notch paralogues that impaired the skin barrier also predisposed Notch1-expressing skin to tumorigenesis, demonstrating that the tumor-promoting effect of Notch1 loss involves a crosstalk between barrier-defective epidermis and its stroma.
Demehri
Shadmehr
S
Department of Developmental Biology, Division of Dermatology, Washington University School of Medicine, Saint Louis, MO 63110-1095, USA.
Turkoz
Ahu
A
Kopan
Raphael
R
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004817:Epidermis / Q000473:pathology; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000172:deficiency* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D018398:Homeodomain Proteins; C084119:MSX2 protein; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate