Letter

A metabolic function of FGFR3-TACC3 gene fusions in cancer

  • Nature volume 553, pages 222227 (11 January 2018)
  • doi:10.1038/nature25171
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Abstract

Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies1,2,3. We have previously described gene fusions of FGFR3-TACC3 (F3–T3) in 3% of human glioblastoma cases4. Subsequent studies have reported similar frequencies of F3–T3 in many other cancers, indicating that F3–T3 is a commonly occuring fusion across all tumour types5,6. F3–T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown2,4,5,6. Here we show that human tumours with F3–T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3–T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3–T3–PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3–T3 and show that F3–T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3–T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.

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Acknowledgements

We thank C. Scuoppo for donation of the pLCiG2 plasmid and support with the gRNA design, E. Chen for identification of PIN4 immunocomplexes and H. Li for high-content microscopy. This work was supported by NIH R01CA101644, U54CA193313 and R01CA131126 to A.L.; R01CA178546, U54CA193313, R01CA179044, R01CA190891, R01NS061776 and The Chemotherapy Foundation to A.I.; SickKids Garron Family Cancer Centre Pitblado Discovery and Ontario Institute for Cancer Research (OICR) Brain Translational Research Initiative to X.H.; American Brain Tumor Association (ABTA) and a Cancer Biology Taining Grant (T32CA009503) fellowship to V.Fra.; a NRF-2013R1A6A3A03063888 fellowship to S.B.L.; an Italian Association for Cancer Research (AIRC) fellowship to M.V.R.

Author information

Author notes

    • Véronique Frattini
    •  & Stefano M. Pagnotta

    These authors contributed equally to this work.

    • Anna Lasorella
    •  & Antonio Iavarone

    These authors jointly supervised this work.

Affiliations

  1. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA

    • Véronique Frattini
    • , Stefano M. Pagnotta
    • , Tala
    • , Marco V. Russo
    • , Sang Bae Lee
    • , Luciano Garofano
    • , Jing Zhang
    • , Peiguo Shi
    • , Genevieve Lewis
    • , Heloise Sanson
    • , Vanessa Frederick
    • , Angelica M. Castano
    • , Anna Lasorella
    •  & Antonio Iavarone
  2. Department of Science and Technology, Universita’ degli Studi del Sannio, Benevento 82100, Italy

    • Stefano M. Pagnotta
    • , Luciano Garofano
    • , Luigi Cerulo
    •  & Michele Ceccarelli
  3. The Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1A4, Canada

    • Jerry J. Fan
    •  & Xi Huang
  4. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

    • Jerry J. Fan
    •  & Xi Huang
  5. BIOGEM Istituto di Ricerche Genetiche ‘G. Salvatore’, Campo Reale, 83031 Ariano Irpino, Italy

    • Luciano Garofano
    • , Luigi Cerulo
    •  & Michele Ceccarelli
  6. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100, USA

    • Delphine C. M. Rolland
    •  & Kojo S. J. Elenitoba-Johnson
  7. Qatar Computing Research Institute (QCRI), Hamad Bin Khalifa University, Doha, Qatar

    • Raghvendra Mall
  8. Sorbonne Universités UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris 75013, France

    • Karima Mokhtari
    •  & Marc Sanson
  9. AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris 75013, France

    • Karima Mokhtari
  10. Onconeurotek, AP-HP, Paris 75013, France

    • Karima Mokhtari
    •  & Marc Sanson
  11. AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France

    • Marc Sanson
  12. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA

    • Anna Lasorella
    •  & Antonio Iavarone
  13. Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA

    • Anna Lasorella
  14. Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA

    • Antonio Iavarone

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Contributions

A.I. and A.L. conceived and coordinated the studies and provided overall supervision. M.C. and S.M.P. developed and performed bioinformatics analyses and wrote the computational sections. V.Fra. performed cell, molecular biology and metabolic assays, with help of T., M.V.R., A.M.C. and S.B.L. J.J.F. and X.H. developed and analysed the Drosophila F3–T3 model. K.S.J.E.-J. and D.M.C.R. conducted the phosphoproteomics experiments. M.S. and K.M. provided GBM tissues and assisted with immunostaining. G.L., T., V.Fre. and H.S. performed immunostaining and protein analyses. T. and P.S. performed mouse experiments. L.G., J.Z., L.C. and R.M. conducted gene expression and bioinformatics analyses. A.I. and A.L. wrote the manuscript with input from all authors.

Competing interests

A.I. and A.L. received research funds from AstraZeneca and Tahio Pharmaceutical Co., Ltd. M.S. is an investigator in two clinical trials using anti-FGFR therapies: AZD4547 (NCT02824133, funded by AstraZeneca) and TAS-120 (NCT02052778, funded by Tahio Pharmaceutical Co., Ltd). The remaining authors declare no competing financial interests.

Corresponding authors

Correspondence to Anna Lasorella or Antonio Iavarone.

Reviewer Information Nature thanks R. Cagan, P. Mischel, M. Ochs and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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