The translational landscape of mTOR signalling steers cancer initiation and metastasis

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. Ribosome profiling reveals specialized translation of the prostate cancer genome by oncogenic mTOR signalling; stringent inhibition of mTOR signalling reduces prostate cancer invasion and metastasis in a mouse model. The mTOR pathway is important in the regulation of protein synthesis and is activated in many human cancers. Two papers in this issue of Nature use ribosome profiling to study the control of messenger RNA translation by mTOR signalling. Hsieh et al. find that in prostate cancer cells and mouse prostate tumours, the translation of several genes involved in cancer invasion is regulated by mTOR by means of the 4EBP1 translational repressor. The experimental drug INK128, currently in clinical trials in people with prostate cancer, inhibits mTOR signalling and reduces the progression of prostate cancers to invasive carcinomas in a mouse model. Thoreen et al. show that through the 4E-BP protein family, the mTORC1 kinase recognizes and regulates a subset of mRNAs with an oligopyrimidine motif at the 5′ end.