Epidermal Notch1 Loss Promotes Skin Tumorigenesis by Impacting the Stromal Microenvironment

Abstract

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 paralogs 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. Significance In contrast to the current dogma, we demonstrate unequivocally that the non-cell autonomous consequences of defective barrier formation are responsible for the tumor-promoting effects of Notch1 loss in mouse skin. Thus, individuals with sub-acute skin-barrier defects may also be prone to carcinogenesis upon exposure to initiating carcinogens like UV rays. As Notch1 deletion in skin tumors enhanced their progression to invasive arcinomas, patients with benign hyperplasic skin lesions receiving γ-secretase inhibitor therapy may, therefore, be at additional risk. More broadly, given that chronic injury causatively effects the development of several human carcinomas, Notch1-deficient mice with mild skin-barrier defects can serve as an experimental model in which to study the tumor-promoting elements of chronic injury/wound and develop relevant therapies.

Development and Homeostasis of the Skin Epidermis

“…Notch deficiency during embryonic development leads to non-cell-autonomous B-cell lymphoproliferative disorder, whereas in adult mice it results in severe atopic dermatitis because of elevated levels of thymic stromal lymphopoietin, possibly because of impaired barrier formation, consistent with the finding that patients suffering from atopic dermatitis have reduced Notch expression in the skin (Dumortier et al 2010). The elevated levels of thymic stromal lymphopoietin may subsequently act systemically and lead to allergic asthma development, explaining the elevated cases of asthma within atopic dermatitis patients (Demehri et al 2009). …”

“…In vitro studies using human keratinocytes have indicated that Notch1 acts as a tumor suppressor gene by up-regulating p21 (Rangarajan et al 2001). However, in vivo studies indicated that Notch1 promotes tumorigenesis in a non-cell-autonomous manner by creating a woundlike microenvironment because of persistent skin barrier defects Demehri et al 2009). In addition to cancer, Notch signaling controls inflammatory responses.…”

Identifying the cellular origin of squamous skin tumors

“…These findings suggested that KRas G12D expression induces migration of bulge SCs toward the SG and the IFE. However, because there is not a perfect correlation between the hyperplastic phenotype and the YFP expression, our data cannot rule out that KRas expression in HF cells promotes epidermal proliferation by a noncellular autonomous mechanism, and thereby promotes tumorigenesis as it occurs after Notch1 deletion in the skin epidermis (35).…”

Tumour–stroma crosstalk in the development of squamous cell carcinoma

“…We have shown NOTCH1 mutation arising in normal and tumor tissue in close proximity suggesting that such a mechanism may be active in human skin (South, Purdie et al 2014). In addition and prior to this work, mosaic loss of NOTCH1 in the epidermal compartment of mice can induce spontaneous tumours competent in Notch1 signaling with data again pointing to a direct influence from the stroma (Demehri, Turkoz et al 2009). …”