A metabolic function of FGFR3-TACC3 gene fusions in cancer

Véronique Frattini, Stefano M. Pagnotta, Tala, Jerry J. Fan, Marco V. Russo, Sang Bae Lee, Luciano Garofano, Jing Zhang, Peiguo Shi, Genevieve Lewis, Heloise Sanson, Vanessa Frederick, Angelica M. Castano, Luigi Cerulo, Delphine C.M. Rolland, RaghvenPhDa Mall, Karima Mokhtari, Kojo S.J. Elenitoba-Johnson, Marc Sanson, Xi Huang & 3 others Michele Ceccarelli, Anna Lasorella, Antonio Iavarone

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23 Citations (Scopus)

Abstract

Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. 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 types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. 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.

Original languageEnglish
Pages (from-to)222-227
Number of pages6
JournalNature
Volume553
Issue number7687
DOIs
Publication statusPublished - 11 Jan 2018

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Gene Fusion
Neoplasms
Oncogene Fusion
Respiration
Phosphopeptides
Genetic Translocation
Peroxisomes
Oxidative Phosphorylation
Organelle Biogenesis
Glioblastoma
Reactive Oxygen Species
Phosphorylation
Therapeutics
Growth

ASJC Scopus subject areas

  • General

Cite this

Frattini, V., Pagnotta, S. M., Tala, Fan, J. J., Russo, M. V., Lee, S. B., ... Iavarone, A. (2018). A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature, 553(7687), 222-227. https://doi.org/10.1038/nature25171

A metabolic function of FGFR3-TACC3 gene fusions in cancer. / Frattini, Véronique; Pagnotta, Stefano M.; Tala; Fan, Jerry J.; Russo, Marco V.; Lee, Sang Bae; Garofano, Luciano; Zhang, Jing; Shi, Peiguo; Lewis, Genevieve; Sanson, Heloise; Frederick, Vanessa; Castano, Angelica M.; Cerulo, Luigi; Rolland, Delphine C.M.; Mall, RaghvenPhDa; Mokhtari, Karima; Elenitoba-Johnson, Kojo S.J.; Sanson, Marc; Huang, Xi; Ceccarelli, Michele; Lasorella, Anna; Iavarone, Antonio.

In: Nature, Vol. 553, No. 7687, 11.01.2018, p. 222-227.

Research output: Contribution to journalArticle

Frattini, V, Pagnotta, SM, Tala, Fan, JJ, Russo, MV, Lee, SB, Garofano, L, Zhang, J, Shi, P, Lewis, G, Sanson, H, Frederick, V, Castano, AM, Cerulo, L, Rolland, DCM, Mall, R, Mokhtari, K, Elenitoba-Johnson, KSJ, Sanson, M, Huang, X, Ceccarelli, M, Lasorella, A & Iavarone, A 2018, 'A metabolic function of FGFR3-TACC3 gene fusions in cancer', Nature, vol. 553, no. 7687, pp. 222-227. https://doi.org/10.1038/nature25171
Frattini V, Pagnotta SM, Tala, Fan JJ, Russo MV, Lee SB et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature. 2018 Jan 11;553(7687):222-227. https://doi.org/10.1038/nature25171
Frattini, Véronique ; Pagnotta, Stefano M. ; Tala ; Fan, Jerry J. ; Russo, Marco V. ; Lee, Sang Bae ; Garofano, Luciano ; Zhang, Jing ; Shi, Peiguo ; Lewis, Genevieve ; Sanson, Heloise ; Frederick, Vanessa ; Castano, Angelica M. ; Cerulo, Luigi ; Rolland, Delphine C.M. ; Mall, RaghvenPhDa ; Mokhtari, Karima ; Elenitoba-Johnson, Kojo S.J. ; Sanson, Marc ; Huang, Xi ; Ceccarelli, Michele ; Lasorella, Anna ; Iavarone, Antonio. / A metabolic function of FGFR3-TACC3 gene fusions in cancer. In: Nature. 2018 ; Vol. 553, No. 7687. pp. 222-227.
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AU - Cerulo, Luigi

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AU - Mokhtari, Karima

AU - Elenitoba-Johnson, Kojo S.J.

AU - Sanson, Marc

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N2 - Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. 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 types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. 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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