RNA sequencing/Gene expression studies of mTORC1 signaling in myeloma
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ABSTRACT:
PROVIDER: PRJNA803990 | ENA |
REPOSITORIES: ENA
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Project description:We determined that mTORC1 is a predominant target of RAS-dependent signaling in multiple myeloma. We sought to obtain a gene signature of mTORC1 activity in myeloma cells by examining changes in gene expression by RNA seq following treatment with the mTORC1 inhibitor everolimus at 100 nM
2022-02-07 | GSE196231 | GEO
Project description:Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1-/- versus Tsc1+/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1-/- cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN. In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.
2019-06-17 | MSV000083988 | MassIVE
Project description:Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.
2022-10-14 | PXD031662 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE25331: Initiation pausing of mRNA translation controlled by mTORC1 signaling (microarray) GSE25626: Initiation pausing of mRNA translation controlled by mTORC1 signaling (RNA-Seq) Refer to individual Series
2011-11-12 | E-GEOD-25627 | biostudies-arrayexpress
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression.
2017-11-28 | GSE67810 | GEO
Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice
2013-06-24 | E-GEOD-46693 | biostudies-arrayexpress
Project description:SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors
| PRJNA450615 | ENA
Project description:The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit. Indeed, such CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern and the molecular mechanisms of such resistance remain undefined. Here, we demonstrate that reactivation of mTORC1 signaling through increased expression of the amino acid transporter, SLC36A1, drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms; 1) Rb loss which drives SLC36A1 via reduced suppression of E2f; 2) FXR1 overexpression which promotes SLC36A1 translation and subsequently mTORC1. Finally, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma.
2021-04-13 | GSE113268 | GEO
Project description:The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the tumor epithelium are poorly understood. The signaling adapter p62 has been implicated as a positive regulator of epithelial tumorigenesis; however, its role in the stroma is unknown. We show here that p62 levels are reduced in the stroma of several tumors. Also, orthotopic and organotypic studies demonstrate that the loss of p62 in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism. Inhibition of the pathway by p62 deficiency results in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through modulation of metabolism in the tumor stroma. C57BL6 syngeneic TRAMP-C2Re3 cells (5×10^4) were injected orthotopically into the prostate of WT (n=6) or p62 KO (n=6) mice (C57BL6 background) and tumor growth was assessed, followed by transcriptome profiling of the orthotopic tumors (n=12).
2014-07-23 | E-GEOD-55587 | biostudies-arrayexpress
Project description:To elucidate enhancers participating in sculpting human face, we performed CAGE-sequencing of facial mesenchyme of human embryos and cross-referenced identified active enhancers against GWAS datasets for human normal-range facial appearance. Among identified single nucleotide polymorphisms (SNPs) in the active cis-enhancers, several belonged to the components of mTORC1 (Mechanistic Target of Rapamycin Complex 1) pathway. To assess the role of this pathway functionally, genetic and pharmacological manipulations of mTORC1 pathway in mice and zebrafish were performed. They revealed the modulatory role of mTORC1 signaling in fine craniofacial shaping.
2024-01-23 | GSE254018 | GEO