Reference : Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
Scientific journals : Article
Life sciences : Anatomy (cytology, histology, embryology...) & physiology
http://hdl.handle.net/2268/190811
Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
English
LADANG, Aurélie* mailto [Centre Hospitalier Universitaire de Liège - CHU > > Frais communs Biologie clinique - Pool assistants >]
Rapino, Francesca* mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Heukamp, Lukas [> >]
Tharun, Lars [> >]
Shostak, Kateryna mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Hermand, Damien [> >]
Delaunay, Sylvain mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Klevernic, Iva mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
Jiang, Zheshen [> >]
Jacques, Nicolas [> >]
Jamart, Diane [> >]
Migeot, Valérie [> >]
Florin, Alexandra [> >]
Goktuna, Serkan [> >]
Malgrange, Brigitte mailto [Université de Liège > > GIGA - Neurosciences >]
Samson, Owen [> >]
Nguyen, Laurent mailto [Université de Liège > > GIGA - Neurosciences >]
Buettner, Reinhard [> >]
Close, Pierre mailto [Université de Liège > Département de pharmacie > Chimie médicale > Co-last author >]
Chariot, Alain mailto [Université de Liège > Département de pharmacie > Chimie médicale >]
* These authors have contributed equally to this work.
16-Nov-2015
Journal of Experimental Medicine
Rockefeller University Press
212
12
ELPING TUMOR INITIATION
2057-75
Yes (verified by ORBi)
International
0022-1007
1540-9538
New York
NY
[en] Sox9 ; tRNA ; Dclk1 ; Elongator ; Elp3 ; intestinal cancer
[en] 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.
Researchers
http://hdl.handle.net/2268/190811
10.1084/jem.20142288
http://reflexions.ulg.ac.be/en/IntestinalCancerELP3

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