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Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium

Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced Hras(G12V) in single murine epidermal cells and followed them long term. We observed that Hras(G12V) promotes an early...

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Autores principales: Sandoval, Madeline, Ying, Zhe, Beronja, Slobodan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817173/
https://www.ncbi.nlm.nih.gov/pubmed/33393458
http://dx.doi.org/10.7554/eLife.54618
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author Sandoval, Madeline
Ying, Zhe
Beronja, Slobodan
author_facet Sandoval, Madeline
Ying, Zhe
Beronja, Slobodan
author_sort Sandoval, Madeline
collection PubMed
description Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced Hras(G12V) in single murine epidermal cells and followed them long term. We observed that Hras(G12V) promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intraclonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of Hras(G12V)-driven differentiation, we screened known Ras-effector in vivo and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.
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spelling pubmed-78171732021-01-21 Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium Sandoval, Madeline Ying, Zhe Beronja, Slobodan eLife Cancer Biology Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced Hras(G12V) in single murine epidermal cells and followed them long term. We observed that Hras(G12V) promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intraclonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of Hras(G12V)-driven differentiation, we screened known Ras-effector in vivo and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation. eLife Sciences Publications, Ltd 2021-01-04 /pmc/articles/PMC7817173/ /pubmed/33393458 http://dx.doi.org/10.7554/eLife.54618 Text en © 2021, Sandoval et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Sandoval, Madeline
Ying, Zhe
Beronja, Slobodan
Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title_full Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title_fullStr Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title_full_unstemmed Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title_short Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
title_sort interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817173/
https://www.ncbi.nlm.nih.gov/pubmed/33393458
http://dx.doi.org/10.7554/eLife.54618
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