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Selective mRNA translation governs the tumor-associated macrophage phenotype

ABSTRACT: Tumor-associated macrophages (TAMs) continuously tune their immune modulatory properties, but how gene expression programs coordinate this is largely unknown. Selective mRNA translation facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs and plays pivotal roles in regulating immune cell plasticity. Using polysome-profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies targeting key cellular functions including cell proliferation and metabolism. These changes in translational efficiencies paralleled accumulation of immunosuppressive macrophages with augmented phosphorylation of eIF4E, a target of the MNK1 and MNK2 kinases, whose altered phosphorylation selectively modulates mRNA translation. Furthermore, suppression of MNK2-signaling reprogrammed immunosuppressive macrophages towards a pro-inflammatory phenotype with the ability to activate CD8+ T cells. Thus, selective changes of mRNA translation depending on MNK2-signaling represents a key node regulating macrophage immunosuppressive functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE151432 | GEO | 2020/12/31

REPOSITORIES: GEO

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Project description:Tuberous sclerosis complex (TSC) is an inherited multi-system disorder caused by mutations in the TSC1 or TSC2 gene. TSC patients are often diagnosed with a range of neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD), intellectual disability (ID), anxiety and mood disorders. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using neural progenitor cells (NPCs) from patient-derived induced pluripotent stem cells (iPSCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in CRISPR-modified TSC1-null NPCs, which were unaffected by mTORC1 inhibition by rapamycin,the only approved therapy for TSC1. Here, to assess TSC1-dependent gene expression programs in NPCs, we used polysome-profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level. In addition to changes in mRNA abundance, this revealed numerous TSC1-dependent alterations in translational efficiencies. To assess the relevance of these gene expression alterations we performed polysome-profiling in post-mortem brains originating from ASD donors and matched controls. Strikingly, TSC1-dependent alterations in mRNA translation observed in NPCs were largely recapitulated in human brains. Furthermore, although polysome-profiling revealed a partial reversal of TSC1-associated gene expression alterations following rapamycin treatment, most genes related to neural activity/synaptic regulation or ASD that showed TSC1-dependent translation were rapamycin-insensitive. Therefore, we also examined whether early ND rapamycin-insensitive phenotypes in TSC1-null NPCs could be rescued by a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272 (Revolution Medicines, Inc.). Unlike rapamycin, RMC-6272 strongly inhibited translation and reversed TSC1-associated proliferation and neurite outgrowth phenotypes. In summary, we reveal ample translational alterations in TSC1 patient-derived NPCs recapitulating human brain expression profiles and potential implications for treatment of TAND.

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Selective mRNA translation governs the tumor-associated macrophage phenotype

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