Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

Narmen Azazmeh; Benjamin Assouline; Eitan Winter; Shmuel Ruppo; Yuval Nevo; Alexander Maly; Karen Meir; Agnieszka K. Witkiewicz; Jonathan Cohen; Sophia V. Rizou; Eli Pikarsky; Chen Luxenburg; Vassilis G. Gorgoulis; Ittai Ben-Porath

doi:10.1038/s41467-020-16475-3

Chronic expression of p16^INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

Narmen Azazmeh, Benjamin Assouline, Eitan Winter, Shmuel Ruppo, Yuval Nevo, Alexander Maly, Karen Meir, Agnieszka K. Witkiewicz, Jonathan Cohen, Sophia V. Rizou, Eli Pikarsky, Chen Luxenburg, Vassilis G. Gorgoulis, Ittai Ben-Porath^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

p16^INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16^INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16^INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16^INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16^INK4a expression, and Wnt inhibition suppresses p16^INK4a-induced hyperplasia. Senolytic treatment reduces p16^INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16^INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16^INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

Original language	American English
Article number	2711
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16475-3
State	Published - 1 Dec 2020

Bibliographical note

Funding Information:
We thank Safa Hirbawi for technical assistance, Norma E. Kidess-Bassir for histological preparation, Sharona Elgavish, and Hadar Benyamini for bioinformatics assistance, Dan Lehmann of the Core Research Facility at Hebrew University for FACS assistance, and Yaron Fuchs for advice. We thank Elaine Fuchs for the tet-Tcf3 mice. This study was supported by grants from the Israel Science Foundation (1009/13, 2092/18) and from the DKFZ-MOST Fund (CA-161) (I.B.), by a fellowship from the Israel Council for Higher Education (N.A.), and by the Welfare Foundation for Social & Cultural Sciences (KIKPE) Greece, and NKUA-SARG Greece, grants No 70/3/8916, 70/3/12128 (V.G.G.).

Publisher Copyright:
© 2020, The Author(s).

Access to Document

10.1038/s41467-020-16475-3

Cite this

Azazmeh, N., Assouline, B., Winter, E., Ruppo, S., Nevo, Y., Maly, A., Meir, K., Witkiewicz, A. K., Cohen, J., Rizou, S. V., Pikarsky, E., Luxenburg, C., Gorgoulis, V. G., & Ben-Porath, I. (2020). Chronic expression of p16^INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation. Nature Communications, 11(1), Article 2711. https://doi.org/10.1038/s41467-020-16475-3

@article{95ab517bc065423dabac0cef709d189e,

title = "Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation",

abstract = "p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.",

author = "Narmen Azazmeh and Benjamin Assouline and Eitan Winter and Shmuel Ruppo and Yuval Nevo and Alexander Maly and Karen Meir and Witkiewicz, {Agnieszka K.} and Jonathan Cohen and Rizou, {Sophia V.} and Eli Pikarsky and Chen Luxenburg and Gorgoulis, {Vassilis G.} and Ittai Ben-Porath",

note = "Funding Information: We thank Safa Hirbawi for technical assistance, Norma E. Kidess-Bassir for histological preparation, Sharona Elgavish, and Hadar Benyamini for bioinformatics assistance, Dan Lehmann of the Core Research Facility at Hebrew University for FACS assistance, and Yaron Fuchs for advice. We thank Elaine Fuchs for the tet-Tcf3 mice. This study was supported by grants from the Israel Science Foundation (1009/13, 2092/18) and from the DKFZ-MOST Fund (CA-161) (I.B.), by a fellowship from the Israel Council for Higher Education (N.A.), and by the Welfare Foundation for Social & Cultural Sciences (KIKPE) Greece, and NKUA-SARG Greece, grants No 70/3/8916, 70/3/12128 (V.G.G.). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16475-3",

language = "American English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Azazmeh, N, Assouline, B, Winter, E, Ruppo, S, Nevo, Y, Maly, A, Meir, K, Witkiewicz, AK, Cohen, J, Rizou, SV, Pikarsky, E, Luxenburg, C, Gorgoulis, VG & Ben-Porath, I 2020, 'Chronic expression of p16^INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation', Nature Communications, vol. 11, no. 1, 2711. https://doi.org/10.1038/s41467-020-16475-3

TY - JOUR

T1 - Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

AU - Azazmeh, Narmen

AU - Assouline, Benjamin

AU - Winter, Eitan

AU - Ruppo, Shmuel

AU - Nevo, Yuval

AU - Maly, Alexander

AU - Meir, Karen

AU - Witkiewicz, Agnieszka K.

AU - Cohen, Jonathan

AU - Rizou, Sophia V.

AU - Pikarsky, Eli

AU - Luxenburg, Chen

AU - Gorgoulis, Vassilis G.

AU - Ben-Porath, Ittai

N1 - Funding Information: We thank Safa Hirbawi for technical assistance, Norma E. Kidess-Bassir for histological preparation, Sharona Elgavish, and Hadar Benyamini for bioinformatics assistance, Dan Lehmann of the Core Research Facility at Hebrew University for FACS assistance, and Yaron Fuchs for advice. We thank Elaine Fuchs for the tet-Tcf3 mice. This study was supported by grants from the Israel Science Foundation (1009/13, 2092/18) and from the DKFZ-MOST Fund (CA-161) (I.B.), by a fellowship from the Israel Council for Higher Education (N.A.), and by the Welfare Foundation for Social & Cultural Sciences (KIKPE) Greece, and NKUA-SARG Greece, grants No 70/3/8916, 70/3/12128 (V.G.G.). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

AB - p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

UR - http://www.scopus.com/inward/record.url?scp=85085751702&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-16475-3

DO - 10.1038/s41467-020-16475-3

M3 - Article

C2 - 32483135

AN - SCOPUS:85085751702

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2711

ER -

Chronic expression of p16^INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this