RNA sequencing/Gene expression studies of mTORC1 signaling in myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196231 | GEO | 2022/02/07
REPOSITORIES: GEO
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Project description:RNA sequencing/Gene expression studies of mTORC1 signaling in myeloma
| PRJNA803990 | ENA
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:We recentlly showed that everolimus, a mTORC1 inhibitor increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis of T-ALL cells.
2023-02-23 | GSE225751 | GEO
Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-bM-^@M-^\low/low/high/lowM-bM-^@M-^] or M-bM-^@M-^\LLHLM-bM-^@M-^]. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb Mouse embryo fibroblasts (MEFs) wild type or deficient in Tsc2 expressing a Tfeb shRNA or scrambled shRNA vector were treated with 25 nM rapamycin or vehicle (methanol) for 24 h under low serum conditions (0.1% FBS)
2011-08-02 | E-GEOD-28021 | biostudies-arrayexpress
Project description:A major driver of multiple myeloma is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employ an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in multiple myeloma to inform precision medicine strategies. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between <I>NRAS</I> and <I>KRAS</I> mutants invisible to the genomic landscape. Transcriptional analysis suggests that aberrant MAPK pathway activation is only present in a fraction of <I>RAS</I>-mutated vs. WT <I>RAS</I> patients. These high-MAPK patients, enriched for <I>NRAS</I> Q61 mutations, have inferior outcomes whereas <I>RAS</I> mutations overall carry no survival impact. We further develop an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. These results may lead to improved stratification of MM patients in clinical trials while also revealing unexplored modes of Ras biology.
2019-03-06 | PXD011551 | Pride
Project description:Ras homolog enriched in brain (Rheb1) is a small GTPase and is known to be a direct activator of mTORC1. Dysregulation of Rheb1 has been shown to impair the cellular-energetic state and cell homeostasis. However, the role of Rheb1 in monocytes/macrophages differentiation and maturation is not clear. Here, we investigate the role of Rheb1 in mouse myelopoiesis using a Rheb1 conditional deletion murine model. We found that the absolute number of macrophages decreased in the bone marrow (BM) of Rheb1-deficient mice. Loss of Rheb1 inhibited the monocyte-to-macrophage differentiation process. Additionally, Rheb1 deletion reduced phagocytosis ability of macrophages by inhibiting the mTORC1 signaling pathway. Furthermore, 3BDO (an activator of mTORC1) rescued the phagocytosis ability of Rheb1-deficient macrophages. Thus, Rheb1 is critical for macrophage production and phagocytosis and executes these activities possibly via mTORC1-dependent pathway.
2018-03-23 | GSE79538 | GEO
Project description:Bone destruction is a hallmark of human myeloma and affects more than 80% of patients. Although it is well established that myeloma cells mediate bone destruction by activating osteoclasts, the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing bone destruction in vivo. CRP binds to surface CD32A/FcRIIA, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Clinical studies examining the relationship between the levels of serum CRP and the numbers of osteolytic bone lesions in newly diagnosed patients support this conclusion.
2017-09-12 | GSE103697 | GEO
Project description:Background: Mechanistic target of rapamycin (mTOR) is a nodal serine/threonine protein kinase critical for the control of fundamental cellular processes. Dysregulated mTOR signalling has been shown in cancer, COPD and idiopathic pulmonary fibrosis (IPF). mTOR forms the catalytic subunit of 2 protein complexes: mTORC1 and mTORC2 which differ in upstream inputs, downstream effects and sensitivity to the allosteric inhibitor rapamycin. Aim: To compare the effects of the mTORC1 inhibitor rapamycin with an ATP-competitive inhibitor of mTORC1/2, AZD8055, on TGFβ1 induced transcriptional responses during myofibroblast differentiation by RNA-Seq analysis. Methods: Primary human lung fibroblasts were treated with TGFβ1 for 24h to induce myofibroblast differentiation and extra cellular matrix (ECM) production in the presence of rapamycin or AZD8055. Fibroblasts were also treated with rapamycin or AZD8055 without TGFβ1. Total mRNA was analysed by RNA-Seq. Results: On a global transcriptomic level, TGFβ1 significantly affected the expression of ~4,200 genes by more than 1.5 fold, of which ~1,100 changes were reversed by pan-mTORC1/2 inhibition, while being insensitive to rapamycin. Only 15 gene changes were reversed exclusively by rapamycin. Analysis of the rapamycin-insensitive, mTOR sensitive myofibroblast transcriptome revealed ECM-receptor interaction, metabolism and actin cytoskeleton regulation as major affected pathways. Conclusions: Our data support the conclusion that therapeutic approaches aimed at interfering with TGFb1 induced myofibroblast differentiation and ECM production require dual mTOR1/2 inhibition and may, in part, explain the lack of clinical efficacy of everolimus in the context of IPF.
2019-05-01 | GSE102674 | GEO
Project description:miRNA expression of myeloma cell lines (MM.1S and KMS-11) cultured with HDAC inhibitors (10 nM panobinostat and 1 uM vorinostat) for 48h.
2024-01-31 | GSE253488 | GEO
Project description:To further explain pathology of mTORC1 -stimulated osteoarthritis, we have employed whole genome microarray expression profiling as a discovery platform to identify miRNAs which involved in development of mTORC1-stimulated osteoarthritis We generated Col2a1-specific deletion of Tsc1 mice. mTORC1 induced miRNAs expression in development of osteoarthritis was measured at eight weeks after birth. Independent experiments were performed using knee joint cartilage from Col2a1Tsc1KO and control mice.
2016-07-30 | E-GEOD-71484 | biostudies-arrayexpress