Sun exposure is a strong risk factor for melanoma (MM)development. Upon UVR exposure melanocytes (MCs) prolif-erate and activate pigmentation pathways. These are protec-tive responses. However excessive or repeated episodes ofUVR-induced MC proliferation may increase MM risk in somecircumstances. Most murine MM models carry mutations inMCs or keratinocytes that result in a MC hyperproliferativephenotype. We have studied MC proliferation in mice after asingle neonatal UVR exposure at post-natal-day-3. 3-5 dayslater, in wild type (wt) neonates, we observed a surprising MCactivation not seen in UVR-treated adult mice. MCs migratedto the epidermal basal layer where they resided for up to twoweeks. In MM-prone transgenics with MC-specific expressionof Hras-G12V or Nras-Q61K, basal layer MCs were hyperacti-vated compared to wt, some remaining at the basal layer formore than a month. Our results suggest that this increase inbasal MCs may not be explained by activation of pre-existingimmature epidermal MCs. Instead, our time-course studiessuggest that the increase is better explained by activation ofhair bulb MCs or bulge MC stem cells, that migrate, via theouter root sheath, to the epidermal basal layer. Surprisingly,MCs in mice carrying a pRb pathway defect (oncogenic Cdk4-R24C) did not show an enhanced response to UVR, whereasthose in p53-null mice were defective in their response. MCsin the MM-prone mice removed pyrimidine dimers efficiently, thus a repair defect cannot explain their sensitivity to UVR-induced transformation. We found that neonatal mouse MCs,unlike those in adults, are characterized by an exquisitesensitivity to UVR-induced proliferation and migration that wehypothesize may partly explain the utility of this form ofexposure for inducing MM in mice. We suggest that sustainedUVR-induced stimulation may prime MCs for transformation ifthey also carry a Ras mutation.
XXth International Pigment Cell Conference & Vth International Melanoma Research Congress, Royton Sapporo, Japan 7-12 May 2018