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Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required fo...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647259/ https://www.ncbi.nlm.nih.gov/pubmed/26527802 http://dx.doi.org/10.1084/jem.20142288 |
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author | Ladang, Aurélie Rapino, Francesca Heukamp, Lukas C. Tharun, Lars Shostak, Kateryna Hermand, Damien Delaunay, Sylvain Klevernic, Iva Jiang, Zheshen Jacques, Nicolas Jamart, Diane Migeot, Valérie Florin, Alexandra Göktuna, Serkan Malgrange, Brigitte Sansom, Owen J. Nguyen, Laurent Büttner, Reinhard Close, Pierre Chariot, Alain |
author_facet | Ladang, Aurélie Rapino, Francesca Heukamp, Lukas C. Tharun, Lars Shostak, Kateryna Hermand, Damien Delaunay, Sylvain Klevernic, Iva Jiang, Zheshen Jacques, Nicolas Jamart, Diane Migeot, Valérie Florin, Alexandra Göktuna, Serkan Malgrange, Brigitte Sansom, Owen J. Nguyen, Laurent Büttner, Reinhard Close, Pierre Chariot, Alain |
author_sort | Ladang, Aurélie |
collection | PubMed |
description | Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine. |
format | Online Article Text |
id | pubmed-4647259 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46472592016-05-16 Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine Ladang, Aurélie Rapino, Francesca Heukamp, Lukas C. Tharun, Lars Shostak, Kateryna Hermand, Damien Delaunay, Sylvain Klevernic, Iva Jiang, Zheshen Jacques, Nicolas Jamart, Diane Migeot, Valérie Florin, Alexandra Göktuna, Serkan Malgrange, Brigitte Sansom, Owen J. Nguyen, Laurent Büttner, Reinhard Close, Pierre Chariot, Alain J Exp Med Research Articles Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine. The Rockefeller University Press 2015-11-16 /pmc/articles/PMC4647259/ /pubmed/26527802 http://dx.doi.org/10.1084/jem.20142288 Text en © 2015 Ladang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Ladang, Aurélie Rapino, Francesca Heukamp, Lukas C. Tharun, Lars Shostak, Kateryna Hermand, Damien Delaunay, Sylvain Klevernic, Iva Jiang, Zheshen Jacques, Nicolas Jamart, Diane Migeot, Valérie Florin, Alexandra Göktuna, Serkan Malgrange, Brigitte Sansom, Owen J. Nguyen, Laurent Büttner, Reinhard Close, Pierre Chariot, Alain Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title | Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title_full | Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title_fullStr | Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title_full_unstemmed | Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title_short | Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine |
title_sort | elp3 drives wnt-dependent tumor initiation and regeneration in the intestine |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647259/ https://www.ncbi.nlm.nih.gov/pubmed/26527802 http://dx.doi.org/10.1084/jem.20142288 |
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