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  • Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.

Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.

Proceedings of the National Academy of Sciences of the United States of America (2020-09-30)
Wouter Laurentius Smit, Claudia Nanette Spaan, Ruben Johannes de Boer, Prashanthi Ramesh, Tânia Martins Garcia, Bartolomeus Joannes Meijer, Jacqueline Ludovicus Maria Vermeulen, Marco Lezzerini, Alyson Winfried MacInnes, Jan Koster, Jan Paul Medema, Gijs Robert van den Brink, Vanesa Muncan, Jarom Heijmans
ABSTRACT

Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic Kras G12D Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.

MATERIALS
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Roche
Anti-Bromodeoxyuridine, from mouse IgG1 (clone: BMC9318)