Vav proteins orchestrate a keratinocyte auto/paracrine program critical for skin tumorigenesis

Cutaneous squamous tumors rely on autocrine/paracrine loops for proper fitness. Targeting this Achilles’ heel is therefore considered a potential avenue for patient treatment. However, the mechanisms that engage and sustain such programs during tumor ontogeny are poorly understood. Here, we show that two Rho/Rac activators, the exchange factors Vav2 and Vav3, control the expression of an epithelial autocrine/paracrine program that regulates keratinocyte survival and proliferation as well as the creation of an inflammatory microenvironment. Vav proteins are also critically involved in some of the subsequent autocrine signaling loops activated in keratinocytes. The genetic inactivation of both Vav proteins reduces tumor multiplicity without hampering skin homeostasis, thus suggesting that pan-specific Vav therapies may be useful in skin tumor prevention and treatment. The dorsal skin of WT and DKO mice (Vav2-/-;Vav3-/-) were treated with either one or four applications of phorbol ester 12-O-tetradecanoylphorbol-13 acetate (TPA) (6.8 nmol in 200 μl acetone) two days after shaving. As control, we applied 200 μl of acetone. Animals were euthanized 24 hours after treatment.