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The translational landscape of mTOR signalling steers cancer initiation and metastasis
Open accessAbstract
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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“Other systemwide studies, including a separate analysis by Schwanhausser et al. (2011), also suggest that the differential regulation of translation may be limited to modest changes at a subset of genes”
From System wide analyses have underestimated protein abundances and the importance of transcription in mammals (2014) · cites this paper as Hsieh et al., 2012
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Metadata
- 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
- Venue
- Nature
- Published
- 2012-02-22
- Volume
- 485
- Issue
- 7396
- Pages
- 55-61
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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