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YAP drives cutaneous squamous cell carcinoma formation and progression

YAP drives cutaneous squamous cell carcinoma formation and progression
YAP drives cutaneous squamous cell carcinoma formation and progression

Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.

2050-084X
Vincent-Mistiaen, Zoé
2cd97c21-65cd-411c-b5cc-f864e13ed271
Elbediwy, Ahmed
d9274a21-c34f-4336-b71f-bced852ac601
Vanyai, Hannah
38f81a19-4b61-45c2-bb53-10ae983b404b
Cotton, Jennifer
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Stamp, Gordon
6a473650-84a6-4ca4-865c-8fc5439a69c4
Nye, Emma
81d13b33-7d53-45e1-b667-7d1d1539411b
Spencer-Dene, Bradley
114178e0-4b17-4cc2-b16f-e9ce9138863b
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Mao, Junhao
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Thompson, Barry
e2305f21-02e2-4c40-be16-5a747afbce9d
Vincent-Mistiaen, Zoé
2cd97c21-65cd-411c-b5cc-f864e13ed271
Elbediwy, Ahmed
d9274a21-c34f-4336-b71f-bced852ac601
Vanyai, Hannah
38f81a19-4b61-45c2-bb53-10ae983b404b
Cotton, Jennifer
6e1e1c78-96d0-4bdf-8d10-328b3bfae582
Stamp, Gordon
6a473650-84a6-4ca4-865c-8fc5439a69c4
Nye, Emma
81d13b33-7d53-45e1-b667-7d1d1539411b
Spencer-Dene, Bradley
114178e0-4b17-4cc2-b16f-e9ce9138863b
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Mao, Junhao
c6f7b776-7d19-438c-94d3-1f68842f5ac8
Thompson, Barry
e2305f21-02e2-4c40-be16-5a747afbce9d

Vincent-Mistiaen, Zoé, Elbediwy, Ahmed, Vanyai, Hannah, Cotton, Jennifer, Stamp, Gordon, Nye, Emma, Spencer-Dene, Bradley, Thomas, Gareth J., Mao, Junhao and Thompson, Barry (2018) YAP drives cutaneous squamous cell carcinoma formation and progression. eLife, 7, [e33304]. (doi:10.7554/eLife.33304).

Record type: Article

Abstract

Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.

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Accepted/In Press date: 29 June 2018
e-pub ahead of print date: 20 September 2018
Published date: September 2018

Identifiers

Local EPrints ID: 427265
URI: http://eprints.soton.ac.uk/id/eprint/427265
ISSN: 2050-084X
PURE UUID: 7bb6e854-7e48-4c81-89af-f0a7bcc875b0

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Date deposited: 10 Jan 2019 17:30
Last modified: 05 Jun 2024 19:29

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Contributors

Author: Zoé Vincent-Mistiaen
Author: Ahmed Elbediwy
Author: Hannah Vanyai
Author: Jennifer Cotton
Author: Gordon Stamp
Author: Emma Nye
Author: Bradley Spencer-Dene
Author: Junhao Mao
Author: Barry Thompson

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