Wnt signaling potentiates nevogenesis

Pawlikowski, J.S., McBryan, T., van Tuyn, J., Drotar, M.E., Hewitt, R.N., Maier, A.B., King, A., Blyth, K. , Wu, H. and Adams, P.D. (2013) Wnt signaling potentiates nevogenesis. Proceedings of the National Academy of Sciences of the United States of America, 110(40), pp. 16009-16014. (doi: 10.1073/pnas.1303491110) (PMID:24043806) (PMCID:PMC3791768)

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Abstract

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pawlikowski, Mr Jeff and Blyth, Professor Karen and King, Dr Ayala and Drotar, Mr Mark and Adams, Professor Peter and van Tuyn, Dr John
Authors: Pawlikowski, J.S., McBryan, T., van Tuyn, J., Drotar, M.E., Hewitt, R.N., Maier, A.B., King, A., Blyth, K., Wu, H., and Adams, P.D.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495301Tumor progression - its antagonistic regulation by Wnt-signalling and oncogene-induced senescence.Peter AdamsCancer Research UK (CAN-RES-UK)C10652/A10250RI CANCER SCIENCES
507822Regulation of oncogene-induced senescence by Wnt-signallingPeter AdamsNational Institute of Health (USA) (NIH(US))7r01ca129334/02RI CANCER SCIENCES