eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Chan, K., Robert, F., Oertlin, C., Kapeller-Libermann, D., Avizonis, D., Gutierrez, J., Handly-Santana, A., Doubrovin, M., Park, J., Schoepfer, C., Da Silva, B., Yao, M., Gorton, F., Shi, J., Thomas, C. J., Brown, L. E., Porco, J. A., Pollak, M., Larsson, O., Pelletier, J., Chio, I. I. C. (November 2019) eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Nat Commun, 10 (1). p. 5151. ISSN 2041-1723

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.

Item Type:	Paper
Additional Information:	Nature communications
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment diseases & disorders > neoplasms organism description > animal Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > cell culture organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > translation
CSHL Authors:	Da Silva, Brandon Schoepfer, Christina Yao, Melissa Gorton, Faith
Communities:	CSHL labs > Tuveson lab
Depositing User:	Adrian Gomez
Date:	13 November 2019
Date Deposited:	22 Nov 2019 15:40
Last Modified:	01 Feb 2024 20:56
PMCID:	PMC6853918
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38711

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