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The translational landscape of mTOR signalling steers cancer initiation and metastasis

Author

Listed:
  • Andrew C. Hsieh

    (Helen Diller Family Comprehensive Cancer Center, University of California
    University of California)

  • Yi Liu

    (Intellikine Inc.)

  • Merritt P. Edlind

    (Helen Diller Family Comprehensive Cancer Center, University of California)

  • Nicholas T. Ingolia

    (Carnegie Institution for Science)

  • Matthew R. Janes

    (Intellikine Inc.)

  • Annie Sher

    (Helen Diller Family Comprehensive Cancer Center, University of California)

  • Evan Y. Shi

    (Helen Diller Family Comprehensive Cancer Center, University of California)

  • Craig R. Stumpf

    (Helen Diller Family Comprehensive Cancer Center, University of California)

  • Carly Christensen

    (Helen Diller Family Comprehensive Cancer Center, University of California)

  • Michael J. Bonham

    (University of California)

  • Shunyou Wang

    (Intellikine Inc.)

  • Pingda Ren

    (Intellikine Inc.)

  • Michael Martin

    (Intellikine Inc.)

  • Katti Jessen

    (Intellikine Inc.)

  • Morris E. Feldman

    (Howard Hughes Medical Institute, University of California)

  • Jonathan S. Weissman

    (Howard Hughes Medical Institute, University of California)

  • Kevan M. Shokat

    (Howard Hughes Medical Institute, University of California)

  • Christian Rommel

    (Intellikine Inc.)

  • Davide Ruggero

    (Helen Diller Family Comprehensive Cancer Center, University of California)

Abstract

The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the ‘cancerous’ translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.

Suggested Citation

  • Andrew C. Hsieh & Yi Liu & Merritt P. Edlind & Nicholas T. Ingolia & Matthew R. Janes & Annie Sher & Evan Y. Shi & Craig R. Stumpf & Carly Christensen & Michael J. Bonham & Shunyou Wang & Pingda Ren &, 2012. "The translational landscape of mTOR signalling steers cancer initiation and metastasis," Nature, Nature, vol. 485(7396), pages 55-61, May.
    • Handle: RePEc:nat:nature:v:485:y:2012:i:7396:d:10.1038_nature10912
    DOI: 10.1038/nature10912
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    Citations

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    Cited by:

    1. Sebastian Castillo-Hair & Stephen Fedak & Ban Wang & Johannes Linder & Kyle Havens & Michael Certo & Georg Seelig, 2024. "Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Guo-dong Cao & Xing-yu Xu & Jia-wei Zhang & Bo Chen & Mao-ming Xiong, 2016. "Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer," PLOS ONE, Public Library of Science, vol. 11(12), pages 1-16, December.
    3. Kathrin Leppek & Gun Woo Byeon & Wipapat Kladwang & Hannah K. Wayment-Steele & Craig H. Kerr & Adele F. Xu & Do Soon Kim & Ved V. Topkar & Christian Choe & Daphna Rothschild & Gerald C. Tiu & Roger We, 2022. "Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Mykola Roiuk & Marilena Neff & Aurelio A. Teleman, 2024. "eIF4E-independent translation is largely eIF3d-dependent," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Fajin Li & Jianhuo Fang & Yifan Yu & Sijia Hao & Qin Zou & Qinglin Zeng & Xuerui Yang, 2023. "Reanalysis of ribosome profiling datasets reveals a function of rocaglamide A in perturbing the dynamics of translation elongation via eIF4A," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Tal Levy & Kai Voeltzke & Laura Hruby & Khawla Alasad & Zuelal Bas & Marteinn Snaebjörnsson & Ran Marciano & Katerina Scharov & Mélanie Planque & Kim Vriens & Stefan Christen & Cornelius M. Funk & Chr, 2024. "mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Stéphanie Kaeser-Pebernard & Christine Vionnet & Muriel Mari & Devanarayanan Siva Sankar & Zehan Hu & Carole Roubaty & Esther Martínez-Martínez & Huiyuan Zhao & Miguel Spuch-Calvar & Alke Petri-Fink &, 2022. "mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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