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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
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.
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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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