Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Asparagine availability governs metastasis in a model of breast cancer

ABSTRACT: Single - cell profiling of patient tumours and of mouse models is revealing that many cancers are constituted of communities of genetically and phenotypically distinct clonal lineages 1 - 12. A functional model of breast cancer heterogeneity revealed that clonal sub - populations proficient at generating circulating tumour cells were not equally capable of forming metastases at secondary sites 13. A combination of differential expression and focused in vitro and in vivo RNAi screens revealed candidate drivers of metastasis discriminating these clones, which were then evaluated in gene expression datasets from breast cancer patients. Among these, Asparagine Synthetase (Asns) expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Silencing of Asns reduced both metastatic potential in vivo and invasive potential in vitro. Conversely, increasing the availability of extracellular asparagine increased the invasive potential of mouse and human breast cancer cells, and enforced Asns expression promoted metastasis. Decreasing asparagine availability in mice by treatment with L-asparaginase or even by dietary restriction strongly reduced metastasis from orthotopic tumours. Asparagine availability varies betwe en tissues, potentially explaining selective effects on particular steps of tumor progression. Asparagine limitation reduced the production of proteins that promote the epithelial to mesenchymal transition, providing one potential mechanism for how the availability of a single amino acid could regulate metastatic progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107109 | GEO | 2018/02/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Asparagine bioavailability governs metastasis in a model of breast cancer

Project description:Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites1. A combination of differential expression and focused in vitro and in vivo RNAi screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, Asparagine Synthetase (ASNS) expression in a patient’s primary tumour was most strongly correlated with later metastatic relapse. Here, we have shown that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by Asns knockdown, treatment with L-asparaginase, or dietary asparagine restriction reduced metastasis without impacting growth of the primary tumour, whereas increased dietary asparagine or enforced Asns expression promoted metastatic progression. Altering asparagine availability in vitro strongly influenced invasive potential, and this was correlated with an impact on proteins that promote the epithelial to mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.

2018-02-07 | PXD008805 | Pride

Analysis of gene expression (RNAseq) from Tp53/Pten DKO and Pten KO tumors 5 months post-castration

Project description:The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we show here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS, the enzyme catalyzing the synthesis of asparagine). Mechanistically, loss/mutation of TP53 transcriptionally activate ASNS expression, directly as well as via ATF4, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells are sensitive to asparagine restriction by knockdown of ASNS and L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine respectively. This effect was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase (GLS) inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for co-targeting intracellular and extracellular asparagine production to treat these lethal prostate cancers.

2022-10-11 | GSE215153 | GEO

Chromatin accessibility profiling by ATAC-seq in LNCaP-shNT and LNCaP-shTP53 cells

2024-02-29 | GSE255000 | GEO

Effect of enforced BMP4 expression on gene expression profile of 4T1.2 whole primary murine mammary tumours

Project description:BMP4 is down-regulated in metastatic human and murine mammary tumours. Here we determined the effect of ectopic mouse Bmp4 re-expression on global gene expression patterns in orthotopic primary mammary tumours in syngeneic Balb/c mice. Breast cancer is a major cause of cancer related death in women, due to the development of metastatic disease in vital organs. Metastasis can be facilitated by tumor induced MDSC, which requires understanding. We have confirmed that BMP4 is a potent suppressor of breast cancer metastasis, but for potential clinical application, it is important to understand how BMP4 acts to suppress metastasis. Here, we report one mechanism by which BMP4 can inhibit metastasis. Mice bearing highly metastatic mammary tumors present with elevated numbers of myeloid derived suppressor cells (MDSC), the extent of which is markedly reduced upon exogenous BMP4 expression. Increased numbers of MDSC can also be induced directly by treatment with granulocyte-colony stimulating factor (G-CSF), leading to enhancement of metastasis. Both tumor-induced and G-CSF-induced MDSC can effectively suppress T cell activation and proliferation. BMP4 acts to reduce the expression and secretion of G-CSF through inhibition of NFkB activity in several human and mouse tumor lines. Since MDSC in breast cancer patients are correlated with poor prognosis, BMP4 treatment offers a potential new therapeutic strategy for progressive breast disease. Three 4T1.2 primary mammary tumours and three 4T1.2-Bmp4 primary mammary tumours were analyzed.

2014-06-01 | E-GEOD-51632 | biostudies-arrayexpress

Asparagine availability governs metastasis in a model of breast cancer

Project description:Asparagine availability governs metastasis in a model of breast cancer

| PRJNA419005 | ENA

mRNA profiling of Asns-silenced murine 4T1-T breast cancer cells grown in the presence and absence of Asparagine

Project description:Murine 4T1-T breast cancer cells were infected with an shRNA targeting Asparagine Synthetase (Asns) and grown in DMEM +/- asparagine. Cells were harvested and processed with the NuGen Ovation RNAseq system V2. Libraries were sequenced on an Illumina platform and mapped using Bowtie2 to the mm10 genome prior to transcript quantification using HT-Count.

2018-02-07 | GSE104964 | GEO

Asparagine availability controlsgerminal centre B cell homeostasis

Project description:Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell. Yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that asparagine metabolism is highly upregulated. Asparagine is conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) is markedly upregulated following their activation, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted, B cell survival in low asparagine conditions is severely impaired. Using stable isotope tracing, we found that metabolic adaptation to the absence of asparagine requires ASNS, and that the synthesis of nucleotides is particularly sensitive to asparagine deprivation. Conditional deletion of Asns in B cells selectively impairs GC formation, associated with a reduction in RNA synthesis rates. Finally, removal of environmental asparagine by asparaginase was found to also severely compromise the GC reaction.

2024-04-03 | GSE228845 | GEO

Effect of enforced BMP4 expression on gene expression profile of 4T1.2 whole primary murine mammary tumours

2014-06-01 | GSE51632 | GEO

Identification of critical therapeutic nodes to overcome Asparagine deprivation resistance in melanoma

Project description:Asparagine deprivation by L-Asparaginase is a successful therapeutic strategy in Acute Lymphoblastic Leukemia, with resistance occurring due to upregulation of ASNS. L-Asparaginase efficacy in solid tumors is hampered by dose-related toxicities. Large scale loss of function genetic screens identified ASNS, the only human enzyme synthetizing asparagine, as a cancer dependency in several solid malignancies, including melanoma. We here evaluate the therapeutic potential of targeting ASNS in melanoma cells in-vitro and in-vivo. Using ex-vivo quantitative proteome and transcriptome profiling, we observed that concomitant ASNS deletion and asparagine deprivation elicit a compensatory mechanism allowing tumor growth. Genome wide CRISPR screens upon manipulation of aminoacid levels identifies MAPK and GCN2 as critical nodes mediating the observed resistance mechanism. Importantly MEK and GCN2 inhibitor synergize with L-Asparaginase suggesting novel potential therapeutic strategy in melanoma.

2022-02-15 | PXD015152 | Pride

Multi-colour lineage tracing reveals intra-stage proliferative heterogeneity during mammary tumour progression

Project description:We have assessed clonal heterogeneity within individual primary tumours and metastasis and also during the distinct stages of malignant tumour progression using the Confetti lineage reporter in the background of the MMTV-PyMT mouse model of metastatic breast cancer. Comparative gene expression analysis of the clonal populations reveals a substantial level of heterogeneity across and also within the various stages of breast carcinogenesis. This intra-stage heterogeneity is manifested by differences in cell proliferation, where the fast-proliferating subclass is further enriched in oxidative phosphorylation and cell death.

2020-10-11 | GSE139390 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data