Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Ladang, A. et al. (2015) Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. Journal of Experimental Medicine, 212(12), pp. 2057-2075. (doi: 10.1084/jem.20142288) (PMID:26527802)

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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:Articles
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Ladang, A., Rapino, F., Heukamp, L. C., Tharun, L., Shostak, K., Hermand, D., Delaunay, S., Klevernic, I., Jiang, Z., Jacques, N., Jamart, D., Migeot, V., Florin, A., Göktuna, S., Malgrange, B., Sansom, O. J., Nguyen, L., Bu ttner, R., Close, P., and Chariot, A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Experimental Medicine
Publisher:Rockefeller University Press
ISSN (Online):1540-9538
Copyright Holders:Copyright © 2015 Ladang et al.
First Published:First published in Journal of Experimental Medicine 212(12):2057-2075
Publisher Policy:Reproduced under a Creative Commons License

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