Chronic expression of the tumor-suppressor p16^INK4a promotes early epidermal tumorigenesis through Wnt-pathway activation

Cellular senescence is a coordinated program activated by cells in response to stress or damage. Senescent cells are detected in various physiological contexts, including age-related pathologies, and often negatively affect disease. In the context of cancer, senescence suppresses tumor development by inducing cell cycle arrest, but can also exert tumor-promoting effects through paracrine mechanisms. Overall, the physiologic effects of tissue resident senescent cells are poorly understood. To study the effects of the presence of senescent cells in the adult epidermis, we developed transgenic mice an inducible p16^INK4a gene. p16^INK4a expression in the epidermis induced cell cycle arrest, cell enlargement, and senescence. Surprisingly, activation of p16^INK4a for 6 months induced epidermal hyperplasia, accompanied by regions of dysplasia. This was caused by a dramatic increase in the proliferation of keratinocytes neighboring p16-expressing cells. Chronic p16 activation also doubled the number of tumors formed in mice in a carcinogen-induced skin cancer model. Profiling of p16^INK4a-expressing cells revealed activation of Wnt pathway ligands and targets. Pharmacologic or genetic inhibition of the Wnt pathway in p16-expressing mice dramatically reduced hyperplasia. These findings altogether indicate that p16^INK4a may promote early stages of skin malignancy by inducing the proliferation of adjacent keratinocytes through Wnt activation. Consistent with this, p16-expressing cells were detected in human premalignant skin lesions (actinic keratosis) often adjacent to proliferating cells. These findings shed new light on the development of early skin malignancies and suggest a novel tumor-promoting role for the p16 tumor-suppressor gene.