Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106869 | GEO | 2019/11/11
REPOSITORIES: GEO
Similar Datasets
Project description:Oncogenic MYC Activates a Feedforward Regulatory Loop Promoting Essential Amino Acid Metabolism and Tumorigenesis
| PRJNA418288 | ENA
Project description:Analysis of murine model of T cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) reveals that primary T-ALL cells have high transport rates for multiple nutrients. In particular, high levels of leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1a (HIF1a) and c-Myc, the drivers of glucose transport. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1a or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the dominant System L-amino acid transporter in primary PTEN-/- T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data highlight the importance of regulated amino acid transport for T cell malignancies and how a single amino acid transporter can play a key role.
2018-10-08 | PXD006209 | Pride
Project description:The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T-cell development and in the pathogenesis over 50% of human T-cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by downregulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. Keywords: Drug treatment
2006-11-13 | GSE5827 | GEO
Project description:T cell clonal expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in CD4+ and CD8+ T cells. Quantitative proteomics was performed on naive wild-type (WT) and 24 hr T cell receptor (TCR) activated Myc WT and Myc-deficient T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that shapes T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to induce amino acid transporter expression. Quantitative proteomics of 24 hr TCR activated Slc7a5 WT and Slc7a5-deficient CD4 T cells reveals that loss of a single Myc-controlled amino transporter, Slc7a5, can effectively phenocopy the impact of Myc deletion. This study thus provides a comprehensive map of how Myc selectively shapes T cell phenotypes and reveals that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs.
2020-02-25 | PXD016105 | Pride
Project description:Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates ?-adrenoceptors (?ARs) to enhance metastasis from primary tumors and that ?-blockers may be protective in breast cancer. However, the subtype of ?AR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the ?2AR is the only functionally relevant ?AR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. ?2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca(2+) (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca(2+) pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the ?2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca(2+) loop (formoterol AUC in the presence of 2'5'-dideoxyadenosine 0.64 ± 0.03, or BAPTA-AM 0.45 ± 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 ± 0.30). Specifically targeting the positive feedforward cAMP/Ca(2+) loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.
| S-EPMC4750412 | biostudies-literature
Project description:Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them ‘addicted’ to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
2020-11-11 | GSE160479 | GEO
Project description:Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to decreased levels of brain BCAAs, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
2016-12-22 | GSE87808 | GEO
Project description:In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC), and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3′UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3′UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3′UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC, and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.
2022-03-10 | PXD030215 | Pride
Project description:Surprisingly little is known about the critical metabolic changes that neural cells have to undergo during development and how even mild, temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically-essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes. But what are the consequences of interfering with this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons perturbs specifically the postnatal metabolic state leading to a shift in lipid metabolism and a stage- and cell-type-specific alteration in neuronal activity patterns, resulting in a long-term circuit dysfunction.
2023-03-29 | GSE218713 | GEO
Project description:Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBP? signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR.
| S-EPMC4975665 | biostudies-literature