eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

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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Cell line source(s) 293T and PhoenixE cells were obtained from ATCC. Murine pancreatic ductal organoid cultures were generated and cultured as described in these two articles PMIDs: 25557080, 27477511. Patient-derived pancreatic cancer cells are gifts from Dr David Tuveson (CSHL). Pancreatic cancer associated fibroblasts were generated as described in this article (PMID 28232471). More information in Methods Section.

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The genotype of each murine organoid line was validated by Transnetyx real-time PCR to ensure they carry mutant alleles of Kras, Trp53 and/or Nrf2, where appropriate. Patient-derived cell lines were characterized by sequencing DNA to confirm that they harbor loci representative of human PDA. Cancer associated fibroblasts (CAFs) were validated by flow cytometry for positive expression of Fibroblast activating protein (FAP). CAFs were genotyped to ensure they do not carry mutant alleles of Kras, Tp53.

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Gender balanced C57B/6J Mus musculus were used in the current study. KrasG12D;p53R172H;PdxCre (KPC) animals were enrolled into therapeutic studies when tumor volumes reach ~270mm3 by ultrasound imaging. Given the tumor latency of the KPC model, this generally corresponds to mice of 4-5 months of age. For orthotopic transplant experiments, 8 week old C57B6/J mice were purchased from Jackson Laboratory and were used.

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