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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 03, 2019 |
| Title |
eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA sequencing of polysome-associated mRNA and total mRNA of treated and untreated normal mouse organoids, as well as treated and untreated pancreatic ductal adenocarcinoma mouse organoids. Each condition and RNA source combination was replicated 3 times, leading to a total of 24 samples.
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| Contributor(s) |
Chan K, Robert F, Oertlin C, Kapeller-Libermann D, Avizonis D, Park J, Schoepfer C, Da Silva B, Yao M, Gorton F, Thomas C, Brown LE, Porco JA Jr, Doubrovin M, Pollak M, Larsson O, Pelletier J, Chio II |
| Citation(s) |
31723131 |
| Submission date |
Jan 18, 2019 |
| Last update date |
Nov 25, 2019 |
| Contact name |
Christian Oertlin |
| E-mail(s) |
christian.oertlin@ki.se
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| Organization name |
Karolinska Institutet
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| Street address |
Tomtebodavägen 23A
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| City |
Stockholm |
| ZIP/Postal code |
17165 |
| Country |
Sweden |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA515945 |
| SRA |
SRP180384 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125380_organoids_expression_data.txt.gz |
3.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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