title: The translational landscape of mTOR signalling steers cancer initiation and metastasis.
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.
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hsieh
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Merritt P
authors.initials: MP
authors.lastname: Edlind
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Ingolia
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Janes
authors.forename: Annie
authors.initials: A
authors.lastname: Sher
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Shi
authors.forename: Craig R
authors.initials: CR
authors.lastname: Stumpf
authors.forename: Carly
authors.initials: C
authors.lastname: Christensen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bonham
authors.forename: Shunyou
authors.initials: S
authors.lastname: Wang
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
authors.forename: Katti
authors.initials: K
authors.lastname: Jessen
authors.forename: Morris E
authors.initials: ME
authors.lastname: Feldman
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016678:Genome / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014176:Protein Biosynthesis; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001583:Benzoxazoles; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D011743:Pyrimidines; D012333:RNA, Messenger; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C572449:sapanisertib; D000225:Adenine