2. Academic Validation
  3. eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

  • Nat Commun. 2019 Nov 13;10(1):5151. doi: 10.1038/s41467-019-13086-5.
Karina Chan 1,  Francis Robert 2,  Christian Oertlin 3,  Dana Kapeller-Libermann 1,  Daina Avizonis 2,  Johana Gutierrez 1,  Abram Handly-Santana 1 4,  Mikhail Doubrovin 5,  Julia Park 4 6,  Christina Schoepfer 4,  Brandon Da Silva 4 7,  Melissa Yao 4,  Faith Gorton 4,  Junwei Shi 8,  Craig J Thomas 9,  Lauren E Brown 10,  John A Porco Jr 10,  Michael Pollak 11,  Ola Larsson 12,  Jerry Pelletier 13,  Iok In Christine Chio 14
Affiliations

Affiliations

  • 1 Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA.
  • 2 Department of Biochemistry, Oncology and Goodman Cancer Centre, McGill University, Montreal, H3G 1Y6, QC, Canada.
  • 3 Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
  • 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
  • 5 Department of Radiology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 6 Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 7 SUNY Downstate College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, 11203, USA.
  • 8 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 9 National Cancer Institute, Rockville, MD, 20850, USA.
  • 10 Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, 02215, USA.
  • 11 Department of Medicine and Oncology, McGill University, Montreal, QC, Canada.
  • 12 Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. [email protected].
  • 13 Department of Biochemistry, Oncology and Goodman Cancer Centre, McGill University, Montreal, H3G 1Y6, QC, Canada. [email protected].
  • 14 Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA. [email protected].
PMID: 31723131 DOI: 10.1038/s41467-019-13086-5
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.

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