Wnt signaling potentiates nevogenesis

Jeff S Pawlikowski, Tony McBryan, John van Tuyn, Mark E Drotar, Rachael N Hewitt, Andrea B Maier, Ayala King, Karen Blyth, Hong Wu, Peter D Adams

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)16009-14
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
Publication statusPublished - 1 Oct 2013

Fingerprint

Melanocytes
Nevus
Cell Aging
Neoplasms
RNA Sequence Analysis
Phenotype
Wnt Signaling Pathway
Secretory Pathway
Oncogenes
Melanoma
Cell Line
Population

Keywords

  • Animals
  • Cell Line, Tumor
  • Cellular Senescence/physiology
  • DNA Primers/genetics
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Melanocytes/cytology
  • Melanoma/etiology
  • Mice
  • Microarray Analysis
  • Nevus/metabolism
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Wnt Signaling Pathway/physiology

Cite this

Pawlikowski, J. S., McBryan, T., van Tuyn, J., Drotar, M. E., Hewitt, R. N., Maier, A. B., ... Adams, P. D. (2013). Wnt signaling potentiates nevogenesis. Proceedings of the National Academy of Sciences of the United States of America, 110(40), 16009-14. https://doi.org/10.1073/pnas.1303491110
Pawlikowski, Jeff S ; McBryan, Tony ; van Tuyn, John ; Drotar, Mark E ; Hewitt, Rachael N ; Maier, Andrea B ; King, Ayala ; Blyth, Karen ; Wu, Hong ; Adams, Peter D. / Wnt signaling potentiates nevogenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 40. pp. 16009-14.
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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.",
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Pawlikowski, JS, McBryan, T, van Tuyn, J, Drotar, ME, Hewitt, RN, Maier, AB, King, A, Blyth, K, Wu, H & Adams, PD 2013, 'Wnt signaling potentiates nevogenesis' Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 40, pp. 16009-14. https://doi.org/10.1073/pnas.1303491110

Wnt signaling potentiates nevogenesis. / Pawlikowski, Jeff S; McBryan, Tony; van Tuyn, John; Drotar, Mark E; Hewitt, Rachael N; Maier, Andrea B; King, Ayala; Blyth, Karen; Wu, Hong; Adams, Peter D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 40, 01.10.2013, p. 16009-14.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Wnt signaling potentiates nevogenesis

AU - Pawlikowski, Jeff S

AU - McBryan, Tony

AU - van Tuyn, John

AU - Drotar, Mark E

AU - Hewitt, Rachael N

AU - Maier, Andrea B

AU - King, Ayala

AU - Blyth, Karen

AU - Wu, Hong

AU - Adams, Peter D

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N2 - 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.

AB - 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.

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KW - Cell Line, Tumor

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KW - DNA Primers/genetics

KW - HEK293 Cells

KW - Humans

KW - Immunoblotting

KW - Immunohistochemistry

KW - Melanocytes/cytology

KW - Melanoma/etiology

KW - Mice

KW - Microarray Analysis

KW - Nevus/metabolism

KW - Real-Time Polymerase Chain Reaction

KW - Sequence Analysis, RNA

KW - Wnt Signaling Pathway/physiology

U2 - 10.1073/pnas.1303491110

DO - 10.1073/pnas.1303491110

M3 - Article

VL - 110

SP - 16009

EP - 16014

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 40

ER -