Cited by 1,313PI3K/AKT/mTOR signaling in cancerRNA and protein synthesis mechanismsRNA modifications and cancer

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The translational landscape of mTOR signalling steers cancer initiation and metastasis

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Hsieh, Andrew C., Liu, Yi, Edlind, Merritt P., Ingolia, Nicholas T., Janes, Matthew R., Sher, Annie, Shi, Evan Y., Stumpf, Craig R., Christensen, Carly, Bonham, Michael J., Wang, Shunyou, Ren, Pingda, Martin, Michael, Jessen, Katti, Feldman, Morris E., Weissman, Jonathan S., Shokat, Kevan M., Rommel, Christian, Ruggero, Davide·2012·Nature

DOI 10.1038/nature10912PMC PMC3663483

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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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1 retracted

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mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery
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Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton
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Authors: Hsieh, A. C., Liu, Y., Edlind, M. P., Ingolia, N. T., Janes, M. R., Sher, A., Shi, E. Y., Stumpf, C. R., Christensen, C., Bonham, M. J., Wang, S., Ren, P., Martin, M., Jessen, K., Feldman, M. E., Weissman, J. S., Shokat, K. M., Rommel, C., & Ruggero, D.
Affiliations: University of California, San Francisco (US)
Intel (United States) (US)
Carnegie Institution for Science (US)
Howard Hughes Medical Institute (US)
Corresponding author: Rommel, Christian
Ruggero, Davide
ORCID: Hsieh, Andrew C.
Liu, Yi
Ingolia, Nicholas T.
Janes, Matthew R.
Stumpf, Craig R.
Ren, Pingda
Weissman, Jonathan S.
Shokat, Kevan M.
Ruggero, Davide
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-02-22
Volume: 485
Issue: 7396
Pages: 55-61
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10912
PMC: PMC3663483
OpenAlex: W1980396381
Cited by: 1,313
References: 40
Citations by year: 2026: 59 · 2025: 64 · 2024: 65 · 2023: 86 · 2022: 92 · 2021: 93 · 2020: 90 · 2019: 96 · 2018: 104 · 2017: 105 · 2016: 94 · 2015: 98 · 2014: 121 · 2013: 108 · 2012: 36
FWCI: 43.69
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (R01CA140456, R01CA154916)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords: mTOR signaling, prostate cancer, metastasis, tumor invasion, translational regulation, ribosome profiling, 4E-BP1, mTORC1, INK128, oncogenic translation, cell proliferation, cancer metabolism
MeSH terms: Adenine, Animals, Benzoxazoles, Cell Movement, Humans, Male, Mice, Inbred C57BL, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphoproteins, Prostatic Neoplasms, Pyrimidines, Repressor Proteins, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Gene Expression Regulation, Neoplastic, Genome, Cell Cycle Proteins, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factors, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Mice, TOR Serine-Threonine Kinases

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The translational landscape of mTOR signalling steers cancer initiation and metastasis

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