The translational landscape of mTOR signalling steers cancer initiation and metastasis

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, Michael Martin, Katti Jessen, Morris E. Feldman, Jonathan S. Weissman, Kevan M. Shokat, Christian Rommel () and Davide Ruggero ()
Additional contact information
Andrew C. Hsieh: Helen Diller Family Comprehensive Cancer Center, 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

Nature, 2012, vol. 485, issue 7396, 55-61

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10912

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