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Cancer Cell. 2009 Jul 7;16(1):55-66. doi: 10.1016/j.ccr.2009.05.016.

Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment.

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Department of Developmental Biology, Division of Dermatology, Washington University School of Medicine, Saint Louis, MO 63110-1095, USA.


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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