Major finding: An altered translational landscape promotes prostate cancer metastasis.
Approach: Ribosome profiling identified mRNA networks translationally controlled by mTOR.
Impact: mTOR ATP site inhibitors block translation of pro-invasion mRNAs.
The mTOR kinase, which is deregulated in the vast majority of advanced human prostate cancers, is a key regulator of protein synthesis via 4EBP1 and p70S6K1/2 phosphorylation. Using ribosome profiling, a method by which deep sequencing of ribosome-protected mRNA fragments allows quantitative assessment of ribosomal engagement at specific mRNAs, Hsieh and colleagues identified gene expression networks that were translationally controlled by mTOR in prostate cancer cells. After a short period of mTOR inhibitor treatment to capture direct translational effects, the authors observed that 144 mRNAs were post-transcriptionally downregulated. A large fraction of these mTOR-responsive mRNAs represented genes required for protein synthesis, providing further understanding of how mTOR increases the translational capacity of cancer cells. Notably, the second-most represented group corresponded to known regulators of cell invasion and metastasis, a subset of which were overexpressed in a prostate cancer mouse model and elevated in a stepwise fashion during human prostate cancer progression. Suppression of these mRNAs, either by siRNA-mediated knockdown or by treatment with INK128, an mTOR ATP site inhibitor currently in clinical trials, reduced prostate cancer cell invasion, and overexpression of these mRNAs increased the invasive capacity of untransformed prostate epithelial cells in an additive manner. Translational regulation of these genes was dependent on 4EBP1, which was specifically blocked in prostate cancer cells as well as other metastatic cancer cell lines by INK128, but not by allosteric mTOR inhibitors. Furthermore, INK128, but not everolimus (RAD001), led to a dramatic decrease in prostatic intraepithelial neoplasia in mice. Strikingly, INK128 also blocked local progression of invasive prostate cancer, suppressing growth and reducing the total number of metastases. These findings reveal a role for mTOR in translational regulation of a metastatic gene expression program and may have implications for the future treatment of metastatic prostate cancer with ATP site mTOR inhibitors.
Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012 Feb 22. [Epub ahead of print].
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