title: Ribosome profiling reveals a cell-type-specific translational landscape in brain tumors.
abstract: Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5'-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation.
authors.affiliation: Departments of Systems Biology.
authors.forename: Christian
authors.initials: C
authors.lastname: Gonzalez
authors.affiliation: Neurological Surgery.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Sims
authors.affiliation: Departments of Systems Biology, Columbia University MD/PhD Program.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hornstein
authors.affiliation: Pathology and Cell Biology.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Mela
authors.affiliation: Pathology and Cell Biology, Graduate PhD Program in Pathobiology and Molecular Medicine.
authors.forename: Franklin
authors.initials: F
authors.lastname: Garcia
authors.affiliation: Pathology and Cell Biology.
authors.forename: Liang
authors.identifier: http://orcid.org/0000-0003-4775-8989
authors.initials: L
authors.lastname: Lei
authors.affiliation: Pediatrics, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Gass
authors.affiliation: Neurological Surgery.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Amendolara
authors.affiliation: Neurological Surgery.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Pathology and Cell Biology, pas2182@columbia.edu pc561@columbia.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Departments of Systems Biology, Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York 10032 pas2182@columbia.edu pc561@columbia.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sims
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*
keywords: cell-type-specific expression; glioblastoma; glioma; ribosome profiling; translational regulation