Human melanocytic nevi result from impaired senescence due to activated Wnt signaling

[摘要] Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or NRAS oncogene and express markers of senescence, including p16INK4A 1-4. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 25% of melanomas are thought to arise in association with a pre-existing nevus 5-9. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. I set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as Cyclin D1 and c-Myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, Cyclin D1 and c-Myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signaling in nevi correlated inversely with nevus maturation, an established dermatopathological parameter linked to clinical benignancy 10,11. Single cell analyses of lone interfollicular epidermal melanocytes and nevus melanocytes in tissue showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16INK4A-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16INK4A-positive, non-malignant melanocytes. I conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of lower malignant potential, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi.

[发布机构] University:University of Glasgow;Department:Institute of Cancer Sciences

[关键词] Senescence, nevi, melanocyte, Wnt signaling