Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC1, but targeting mutant KRAS has proved challenging2. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases3,4. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling5,6. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras1 (KrasG12D, herein KRas) in a p53LoxP/WT background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Complete transcriptomic profiles are available in the Gene Expression Omnibus under accession number GSE58307.

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Acknowledgements

We thank A. Divakaruni, J. Dunn, C. Smith, K. McGirr and D. Ferrick for their support with the Seahorse Bioscience XF96 Analyser; T. Tieu for vector cloning and J. Kovacs for support with the YSI analyser; J. D. Lechleiter for the protocol to measure mitochondrial potential in vivo; H. Sandoval, C. Tacchetti, M. E. Di Francesco, J. Marszalek and P. Jones for discussions and suggestions; K. Dunner Jr and the High Resolution Electron Microscopy Facility at the MD Anderson Cancer Center (MDACC) for TEM (Cancer Center Core Grant CA16672); W. N. Hittelman and the Center for Targeted Therapy for confocal microscopy; the Dana-Farber Cancer Institute Microarray Core Facility for Affymetrix expression profiling and the MDACC Sequencing and Microarray Facility (SMF) funded by National Cancer Institute (NCI) grant CA016672 (SMF) for exome sequencing; the MDACC Flow Cytometry and Cellular Imaging Core Facility supported by grant NCI#P30CA16672 for flow cytometers and FACS; D. Jayanta for providing GFP–LC3 constructs; B. Perrazzona, U. Varadarajan and R. Dewan for lab management; and S. Jiang for assistance in maintenance of mouse colonies. A.V. is thankful to A. Fantino, S. Rapi, V. Giuliani and P. Viale for their continuous support. This study was supported by grants from the Hirshberg Foundation for Pancreatic Cancer Research to A.V., Harvard Stem Cell Institute to R.A.D. and A.V., Sheikh Ahmed Center for Pancreatic Cancer Research to G.F.D., T.P.H. and A.V., American Italian Cancer Foundation to G.F.D., National Institutes of Health (NIH) P01CA117969 to R.A.D., NIH/NCI P01CA120964 to J.M.A., The Viragh Family Foundation to J.B.F.; C.A.L. is a Pancreatic Cancer Action Network-AACR Pathway to Leadership Fellow.

Author information

Author notes

    • Andrea Viale
    •  & Piergiorgio Pettazzoni

    These authors contributed equally to this work.

Affiliations

  1. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Andrea Viale
    • , Piergiorgio Pettazzoni
    • , Haoqiang Ying
    • , Nora Sánchez
    • , Matteo Marchesini
    • , Alessandro Carugo
    • , Tessa Green
    • , Florian Muller
    • , Simona Colla
    • , Luigi Nezi
    • , Giannicola Genovese
    • , Angela K. Deem
    • , Avnish Kapoor
    • , Wantong Yao
    • , Y. Alan Wang
    •  & Giulio F. Draetta
  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Andrea Viale
    • , Piergiorgio Pettazzoni
    • , Nora Sánchez
    • , Matteo Marchesini
    • , Alessandro Carugo
    • , Tessa Green
    • , Luigi Nezi
    • , Wantong Yao
    •  & Giulio F. Draetta
  3. Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Costas A. Lyssiotis
    •  & Lewis C. Cantley
  4. Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy

    • Alessandro Carugo
  5. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Sahil Seth
    • , Virginia Giuliani
    • , Maria Kost-Alimova
    •  & Timothy P. Heffernan
  6. Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy

    • Emanuela Brunetto
  7. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Ya’an Kang
    •  & Jason B. Fleming
  8. Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

    • Min Yuan
    •  & John M. Asara
  9. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Alec C. Kimmelman
  10. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Huamin Wang
  11. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Ronald A. DePinho

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Contributions

A.V., P.G., R.A.D. and G.F.D. designed the studies, interpreted the data and wrote the manuscript; A.V., P.G., H.Y., N.S., M.M., A.C., T.G. and V.G. performed the experiments; C.A.L. was responsible for metabolomics and carbon-13 tracing experiments; S.S. was responsible for CNV and bioinformatics analysis; M.K.-A, F.M., S.C., L.N., G.G., A.K.D., A.K., W.Y., E.B., Y.K., T.P.H., A.C.K., H.W. and J.B.F. contributed essential reagents and resources; M.Y. and J.M.A. helped with the metabolomics analysis; F.M., Y.A.W. and L.C.C. assisted with data interpretation; A.K.D. edited the manuscript.

Competing interests

L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes in order to disrupt tumour cell growth and survival.

Corresponding authors

Correspondence to Andrea Viale or Giulio F. Draetta.

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https://doi.org/10.1038/nature13611

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