[PDF][PDF] Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment

S Demehri, A Turkoz, R Kopan - Cancer cell, 2009 - cell.com
S Demehri, A Turkoz, R Kopan
Cancer cell, 2009cell.com
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 …
Summary
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.
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