MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA597163 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10753547.fastq.gz | Fastqsanger.gz | |||
| SRR10753549.fastq.gz | Fastqsanger.gz | |||
| SRR10753550.fastq.gz | Fastqsanger.gz | |||
| SRR10753551.fastq.gz | Fastqsanger.gz | |||
| SRR10753552.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:PURPOSE:Small-cell lung cancer (SCLC) has been treated clinically as a homogeneous disease, but recent discoveries suggest that SCLC is heterogeneous. Whether metabolic differences exist among SCLC subtypes is largely unexplored. In this study, we aimed to determine whether metabolic vulnerabilities exist between SCLC subtypes that can be therapeutically exploited. EXPERIMENTAL DESIGN:We performed steady state metabolomics on tumors isolated from distinct genetically engineered mouse models (GEMM) representing the MYC- and MYCL-driven subtypes of SCLC. Using genetic and pharmacologic approaches, we validated our findings in chemo-naïve and -resistant human SCLC cell lines, multiple GEMMs, four human cell line xenografts, and four newly derived PDX models. RESULTS:We discover that SCLC subtypes driven by different MYC family members have distinct metabolic profiles. MYC-driven SCLC preferentially depends on arginine-regulated pathways including polyamine biosynthesis and mTOR pathway activation. Chemo-resistant SCLC cells exhibit increased MYC expression and similar metabolic liabilities as chemo-naïve MYC-driven cells. Arginine depletion with pegylated arginine deiminase (ADI-PEG 20) dramatically suppresses tumor growth and promotes survival of mice specifically with MYC-driven tumors, including in GEMMs, human cell line xenografts, and a patient-derived xenograft from a relapsed patient. Finally, ADI-PEG 20 is significantly more effective than the standard-of-care chemotherapy. CONCLUSIONS:These data identify metabolic heterogeneity within SCLC and suggest arginine deprivation as a subtype-specific therapeutic vulnerability for MYC-driven SCLC.
| S-EPMC6697617 | biostudies-literature
Project description:We report ChIP-Seq analyses for MYC and H3K27Ac in tumors from our MYC-driven genetically engineered mouse model of small cell lung cancer (SCLC) infected with Ad-Cgrp-Cre
2019-12-22 | GSE142496 | GEO
Project description:Metabolically engineered Corynebacterium glutamicum strains were constructed for the enhanced production of L-arginine, and their gene expression profiles were investigated Gene expression profiles of two C. glutamicum strains AR2 and AR6 were examined for the 3043 genes twice.
2013-11-26 | E-GEOD-52737 | biostudies-arrayexpress
Project description:Metabolically engineered Corynebacterium glutamicum strains were constructed for the enhanced production of L-arginine, and their gene expression profiles were investigated
2013-11-26 | GSE52737 | GEO
Project description:Lung macrophages mediate helminth resistance through differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion
2022-01-13 | GSE189674 | GEO
Project description:Transcriptional profiling of MDA-MB-231 and its ρ0 cells (lacking mtDNA) after 48h arginine depletion by arginine deiminase (ADI).
| PRJNA408268 | ENA
Project description:In this study, the effect of arginine deprivation on global gene expression in MDA-MB-231 and its ρ0 cells were examined. MDA-MB-231 ρ0 cells lack mitochondrial DNA and therefore have impaired OXPHOS function. Both parental and ρ0 cells were cultured in complete or arginine depleted medium for 48 hours. Comparative transcriptome analysis of both cell lines in complete growth medium versus arginine depleted medium were performed.
2018-11-02 | GSE104105 | GEO
Project description:Depletion of Nrf2 leads to an increase in cellular ROS, reduced glutathione and thiols, and profound reprogramming of metabolism. Unbiased transcriptome analyses show that key enzymes of glycolysis, pentose phosphate pathway, and glutathione cycle are significantly downregulated, while enzymes of arginine and medium-chain fatty acids metabolism are upregulated. Besides glutamine, pancreatic cancer cells deficient of Nrf2 axis become highly dependent on arginine, which is channelled into the synthesis of phosphocreatine and polyamines. Key enzymes of the creatine pathway, gatm and ckb, are more expressed and more active in Nrf2(-/-) than in WT cells. This metabolism shift creates an energy buffer that enables pancreatic cancer cells to handle increased energy demand. Metabolomic analysis showed that 12% of the creatine pool is phosphorylated in Nrf2(-/-) cells, while the level drops to < 0.1% in WT cells. The inhibition of the creatine pathway with cyclocreatine in Nrf2(-/-) cells, reduces by 43% the ATP level and by 70% invasion rate in matrigel. Furthermore, we found that combination therapies that can target simultaneously the creatine pathway and the KRAS G12D-Nrf2 axis produce a stronger anticancer effect than monotherapies. Taken together, our data provide the basis for the rationale design of new combination therapies against pancreatic cancer. The KRAS G12D-Nrf2 axis controls redox homeostasis and metabolism in PDAC cells. Suppression of KRAS G12D-Nrf2 decreases glycolysis, PPP and glutathione cycle and promotes a metabolic shift of arginine into the synthesis of phosphocreatine
2023-12-12 | GSE217965 | GEO
Project description:Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from individuals spanning the neuropathological progression of AD. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. The brain tissue used in this study were sourced from the Biobank for Aging Studies (LIM-22) in the Department of Pathology at the University of Sao Paulo, as well as from the Neurodegenerative Diseases Brain Bank in the Memory and Aging Center at the University of California, San Francisco. Detailed neuropathological, clinical and genetic data are available under request. Please contact gerolab@gmail.com and lea.grinberg@ucsf.edu.
2020-04-05 | GSE147528 | GEO
Project description:BACKGROUND:MYC amplification or overexpression is common in Group 3 medulloblastoma and is associated with the worst prognosis. Recently, protein arginine methyl transferase (PRMT) 5 expression has been closely associated with aberrant MYC function in various cancers, including brain tumors such as glioblastoma. However, the role of PRMT5 and its association with MYC in medulloblastoma have not been explored. Here, we report the role of PRMT5 as a novel regulator of MYC and implicate PRMT5 as a potential therapeutic target in MYC-driven medulloblastoma. METHODS:Expression and association between PRMT5 and MYC in primary medulloblastoma tumors were investigated using publicly available databases. Expression levels of PRMT5 protein were also examined using medulloblastoma cell lines and primary tumors by western blotting and immunohistochemistry, respectively. Using MYC-driven medulloblastoma cells, we examined the physical interaction between PRMT5 and MYC by co-immunoprecipitation and co-localization experiments. To determine the functional role of PRMT5 in MYC-driven medulloblastoma, PRMT5 was knocked-down in MYC-amplified cells using siRNA and the consequences of knockdown on cell growth and MYC expression/stability were investigated. In vitro therapeutic potential of PRMT5 in medulloblastoma was also evaluated using a small molecule inhibitor, EPZ015666. RESULTS:We observed overexpression of PRMT5 in MYC-driven primary medulloblastoma tumors and cell lines compared to non-MYC medulloblastoma tumors and adjacent normal tissues. We also found that high expression of PRMT5 is inversely correlated with patient survival. Knockdown of PRMT5 using siRNA in MYC-driven medulloblastoma cells significantly decreased cell growth and MYC expression. Mechanistically, we found that PRMT5 physically associated with MYC by direct protein-protein interaction. In addition, a cycloheximide chase experiment showed that PRMT5 post-translationally regulated MYC stability. In the context of therapeutics, we observed dose-dependent efficacy of PRMT5 inhibitor EPZ015666 in suppressing cell growth and inducing apoptosis in MYC-driven medulloblastoma cells. Further, the expression levels of PRMT5 and MYC protein were downregulated upon EPZ015666 treatment. We also observed a superior efficacy of this inhibitor against MYC-amplified medulloblastoma cells compared to non-MYC-amplified medulloblastoma cells, indicating specificity. CONCLUSION:Our results reveal the regulation of MYC oncoprotein by PRMT5 and suggest that targeting PRMT5 could be a potential therapeutic strategy for MYC-driven medulloblastoma.
| S-EPMC6836472 | biostudies-literature