Universität zu Köln

Ladang, Aurelie, Rapino, Francesca ORCID: 0000-0002-4343-3805, Heukamp, Lukas C., Tharun, Lars, Shostak, Kateryna, Hermand, Damien, Delaunay, Sylvain ORCID: 0000-0003-1077-829X, Klevernic, Iva, Jiang, Zheshen ORCID: 0000-0002-4914-7041, Jacques, Nicolas, Jamart, Diane, Migeot, Valerie, Florin, Alexandra, Goktuna, Serkan ORCID: 0000-0001-6169-768X, Malgrange, Brigitte, Sansom, Owen J. ORCID: 0000-0001-9540-3010, Nguyen, Laurent ORCID: 0000-0002-8560-3008, Buettner, Reinhard, Close, Pierre and Chariot, Alain (2015). Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med., 212 (12). S. 2057 - 2076. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ladang, Aurelie UNSPECIFIED UNSPECIFIED UNSPECIFIED Rapino, Francesca UNSPECIFIED orcid.org/0000-0002-4343-3805 UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tharun, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Shostak, Kateryna UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermand, Damien UNSPECIFIED UNSPECIFIED UNSPECIFIED Delaunay, Sylvain UNSPECIFIED orcid.org/0000-0003-1077-829X UNSPECIFIED Klevernic, Iva UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Zheshen UNSPECIFIED orcid.org/0000-0002-4914-7041 UNSPECIFIED Jacques, Nicolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Jamart, Diane UNSPECIFIED UNSPECIFIED UNSPECIFIED Migeot, Valerie UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Goktuna, Serkan UNSPECIFIED orcid.org/0000-0001-6169-768X UNSPECIFIED Malgrange, Brigitte UNSPECIFIED UNSPECIFIED UNSPECIFIED Sansom, Owen J. UNSPECIFIED orcid.org/0000-0001-9540-3010 UNSPECIFIED Nguyen, Laurent UNSPECIFIED orcid.org/0000-0002-8560-3008 UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Close, Pierre UNSPECIFIED UNSPECIFIED UNSPECIFIED Chariot, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-386989
DOI:	10.1084/jem.20142288
Journal or Publication Title:	J. Exp. Med.
Volume:	212
Number:	12
Page Range:	S. 2057 - 2076
Date:	2015
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-9538
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STEM-CELL POPULATIONS; BETA-CATENIN; COLON-CANCER; TUFT CELLS; TRANSCRIPTION FACTOR; IN-VITRO; SOX9; CRYPT; ELONGATOR; MOUSE Multiple languages Immunology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38698