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The translational landscape of mTOR signalling steers cancer initiation and metastasis

Nature volume 485, pages 55–61 (2012)Cite this article

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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.

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Figure 1: Ribosome profiling reveals mTOR-dependent specialized translational control of the prostate cancer genome.
Figure 2: mTOR promotes prostate cancer cell migration and invasion through a translationally regulated gene signature.
Figure 3: The 4EBP1–eIF4E axis controls the post-transcriptional expression of mTOR-sensitive invasion genes.
Figure 4: mTOR hyperactivation augments translation of YB1, MTA1, CD44 and vimentin mRNAs in a subset of pre-invasive prostate cancer cells in vivo.
Figure 5: Complete mTOR inhibition by INK128 treatment prevents prostate cancer invasion and metastasis in vivo.

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Gene Expression Omnibus

Data deposits

Small-RNA sequencing data were deposited in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE35469.

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Acknowledgements

We thank M. Barna for critical discussion and reading of this manuscript; T. Wilson for support and advice; T. Sanders and E. Llagostera-Martin for technical support with confocal microscopy; L. Li, E. Ulm, L. Kessler, J. Kucharski and L. Darjania for technical support for the discovery and development of INK128. J. Kurhanewicz and R. Bok of the Surbeck Institute for Advanced Imaging for technical support and MRI images; N. Sonenberg for providing the 4EBP1/2 double knockout mouse embryonic fibroblasts; J. M. Shen for support; and K. Tong for editing the manuscript. A.C.H. is supported in part by the American Cancer Society (119084-PF-10-233-01-TBE), and is a Prostate Cancer Foundation Young Investigator, and a recipient of the DOD Prostate Cancer Training Award. This work is supported by NIH R01 CA154916 (D.R.), NIH R01 CA140456 (D.R.) and the Phi Beta Psi Sorority (D.R.). D.R. is a Leukemia & Lymphoma Society Scholar.

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Author notes

  1. Andrew C. Hsieh and Yi Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 94158, California, USA

    Andrew C. Hsieh, Merritt P. Edlind, Annie Sher, Evan Y. Shi, Craig R. Stumpf, Carly Christensen & Davide Ruggero

  2. Division of Hematology/Oncology and Department of Internal Medicine, University of California, San Francisco, 94143, California, USA

    Andrew C. Hsieh

  3. Intellikine Inc., La Jolla, 92037, California, USA

    Yi Liu, Matthew R. Janes, Shunyou Wang, Pingda Ren, Michael Martin, Katti Jessen & Christian Rommel

  4. Carnegie Institution for Science, Baltimore, 21218, Maryland, USA

    Nicholas T. Ingolia

  5. Department of Pathology, University of California, San Francisco, 94143, California, USA

    Michael J. Bonham

  6. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, 94158, California, USA

    Morris E. Feldman, Jonathan S. Weissman & Kevan M. Shokat

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Contributions

A.C.H. and D.R. conceived the experiments. A.C.H., M.P.E., M.R.J., A.S., E.Y.S., C.R.S., C.C. and S.W. performed the experiments, PtenL/L preclinical trials, and collected the data. N.T.I. and J.S.W. contributed to ribosomal profiling data analysis. M.J.B. provided pathology support. Y.L., P.R., M.M., S.W., K.J., M.E.F., K.M.S. and C.R. developed and/or supported development of INK128, conducted pharmacokinetic, pharmacodynamic and preclinical studies. A.C.H. and D.R. analysed the data and wrote the manuscript. All authors discussed results and edited the manuscript.

Corresponding authors

Correspondence to Christian Rommel or Davide Ruggero.

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Competing interests

Y.L., M.R.J., S.W., P.R., M.M., K.J. and C.R. are employees of Intellikine, Inc. K.M.S. is a stockholder and consultant for Intellikine.

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Hsieh, A., Liu, Y., Edlind, M. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012). https://doi.org/10.1038/nature10912

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