Article | Published:

PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis

Nature Cell Biology volume 16, pages 9921003 (2014) | Download Citation

  • A Corrigendum to this article was published on 31 October 2014

This article has been updated

Abstract

Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1α) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1α in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1α are also essential for functional motility of cancer cells and metastasis.

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Change history

  • 25 September 2014

    In the version of this Article originally published, the number of patients who were PGC-1α- with detected CTCs in Fig. 8f should have read 'n = 2 (18.2%)'. This error has now been corrected in the online version of the Article.

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Acknowledgements

This study was primarily supported by funds from the Cancer Prevention and Research Institute of Texas and funds from MD Anderson Cancer Center (MDACC). J.T.O’C. was financially supported by the DoD Breast Cancer Research Predoctoral Traineeship Award (W81XWH-09-1-0008). R.K. is supported by NIH Grants CA125550, CA155370, CA151925, DK081576 and DK055001. Mass spectrometry work was partially supported by CA12096405 (J.M.A.) and CA00651646 (J.M.A.). We wish to thank B. Spiegelman and J. Estall (Dana Farber Cancer Institute, Boston, Massachusetts, USA) for providing us with reagents related to PGC-1α. We thank M. Protopopova (MDACC, Houston, Texas) and F. Muller (MDACC, Houston, Texas) for their help with the Seahorse experiments. We thank L. Cantley (BIDMC, Boston, Massachusetts) for his critical reading of the manuscript. We also thank M. Yuan and S. Breitkopf (BIDMC, Boston, Massachusetts) for their help with mass spectrometry experiments, and G. Buruzula and J. LaVecchio at the Joslin Flow Cytometry Core Facility (Joslin Diabetes Center, Boston, Massachusetts) for helping with flow cytometry experiments. For electron microscopy imaging, the High Resolution Electron Microscopy Facility at UTMDACC is supported by the Institutional Core Grant CA16672. We thank R. Langley for help in editing of the manuscript.

Author information

Affiliations

  1. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

    • Valerie S. LeBleu
    •  & Raghu Kalluri
  2. Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

    • Valerie S. LeBleu
    • , Joyce T. O’Connell
    •  & Raghu Kalluri
  3. Department of Cell Biology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Karina N. Gonzalez Herrera
    •  & Marcia C. Haigis
  4. Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52 D-20246 Hamburg, Germany

    • Harriet Wikman
    •  & Klaus Pantel
  5. International Research Center, A. C. Camargo Cancer Center, 01509-010, Sao Paulo, Brazil

    • Fernanda Machado de Carvalho
    • , Aline Damascena
    • , Ludmilla Thome Domingos Chinen
    •  & Rafael M. Rocha
  6. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

    • John M. Asara
  7. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • John M. Asara

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Contributions

J.T.O’C. performed data analyses and helped with the preparation of figures; K.N.G.H. performed experiments; H.W., K.P. and M.C.H. helped with data analyses; F.M.d.C., L.T.D.C., R.M.R. and J.M.A. performed experiments and analysed data, A.D. performed statistical analyses, V.S.L. performed experiments, analysed the data and contributed to the design of the experiment, writing of the manuscript and preparation of figures, R.K. contributed to the conceptual design of the study and provided advice regarding experiments and writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Raghu Kalluri.

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DOI

https://doi.org/10.1038/ncb3039

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