Erratum: Asparagine bioavailability governs metastasis in a model of breast cancer

Knott, Simon; Wagenblast, Elvin; Khan, Showkhin; Kim, Sun Y.; Soto, Mar; Wagner, Michel; Turgeon, Marc-Olivier; Fish, Lisa; Erard, Nicolas; Gable, Annika L.; Maceli, Ashley R.; Dickopf, Steffen; Papachristou, Evangelia K.; D’Santos, Clive S.; Carey, Lisa A.; Wilkinson, John E.; Harrell, J. Chuck; Perou, Charles M.; Goodarzi, Hani; Poulogiannis, George; Hannon, Gregory J.

doi:10.1038/nature26162

Cited by 11 publications

(10 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both L-asparagine and putrescine have been implicated in the promotion of cell growth [54][55][56][57][58][59] . Our data indicates cell lines with higher levels of NAT1 activity have increased amounts of N-acetylated asparagine and putrescine while cell lines with decreased and knocked-out NAT1 activity have decreased amounts of N-acetylated asparagine and putrescine.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that intracellular asparagine exchanges with extracellular amino acids to promote mTORC1 activation, protein and nucleotide synthesis and cell proliferation under normal growth www.nature.com/scientificreports www.nature.com/scientificreports/ (non-starvation) conditions 55 . Additionally, it has been reported that the invasiveness of a mouse breast cancer model could be modulated either by altering asparagine biosynthetic capacity or by modifying extracellular asparagine pools with decreases in asparagine leading to decreased metastatic burden 54 . Polyamines, such as putrescine, are known to facilitate the interactions of transcription factors, such as estrogen receptors with their specific response element and are involved in the proliferation of ER negative breast cancer tumor cells (reviewed in 60 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism

Carlisle

Trainor

Hong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Human arylamine N-acetyltransferase 1 (NAT1), present in all tissues, is classically described as a phase-II xenobiotic metabolizing enzyme but can also catalyze the hydrolysis of acetyl-Coenzyme A (acetyl-CoA) in the absence of an arylamine substrate using folate as a cofactor. NAT1 activity varies inter-individually and has been shown to be overexpressed in estrogen receptor-positive (ER+) breast cancers. NAT1 has also been implicated in breast cancer progression however the exact role of NAT1 remains unknown. The objective of this study was to evaluate the effect of varying levels of NAT1 Nacetylation activity in MDA-MB-231 breast cancer cells on global cellular metabolism and to probe for unknown endogenous NAT1 substrates. Global, untargeted metabolomics was conducted via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) on MDA-MB-231 breast cancer cell lines constructed with siRNA and CRISPR/Cas9 technologies to vary only in NAT1 N-acetylation activity. Many metabolites were differentially abundant in NAT1-modified cell lines compared to the Scrambled parental cell line. N-acetylasparagine and N-acetylputrescine abundances were strongly positively correlated (r = 0.986 and r = 0.944, respectively) with NAT1 N-acetylation activity whereas saccharopine abundance was strongly inversely correlated (r = −0.876). Two of the most striking observations were a reduction in de novo pyrimidine biosynthesis and defective β-oxidation of fatty acids in the absence of NAT1. We have shown that NAT1 expression differentially affects cellular metabolism dependent on the level of expression. Our results support the hypothesis that NAT1 is not just a xenobiotic metabolizing enzyme and may have a role in endogenous cellular metabolism. Breast cancer is a heterogeneous disease with many underlying genetic transformations that lead to a diseased state. According to the American Cancer Association, 30% of all new cancer cases in women in 2020 will be breast cancer and 1 in 8 women will develop breast cancer in their lifetime 1. A better understanding of the role NAT1 has in breast cancer would aide in the development of novel treatment strategies and therapeutics. Human arylamine N-acetyltransferase 1 (NAT1) is a phase-II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-Coenzyme A (acetyl-CoA) in the absence of an arylamine substrate using folate as a co-factor 2,3. Many additional novel roles for NAT1 have recently been identified using breast cancer cell models including regulation of matrix metalloproteinase 9 (MMP9) 4 , providing protection against reactive oxygen species during glucose starvation 5 , and the loss of NAT1 leading to regulation of mitochondria through inhibition of the pyruvate dehydrogenase complex 6. NAT1 expression varies

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism

Carlisle

Trainor

Hong

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Furthermore, studies performed in endothelial cells, Kaposi's sarcoma-associated herpesvirus (KSHV)transformed cancer cells and several normal fibroblast or epithelial cell lines reported a similar effect of asparagine on supporting cell survival and protein translation after glutamine deprivation 44,49,50 . Interestingly, high intracellular asparagine levels have recently been identified to be essential for breast cancer metastasis 51 . This study suggested that L-asparaginase treatment alone can reduce the incidence of breast cancer metastasis to the lung without affecting primary tumor growth.…”

Section: Asparaginementioning

confidence: 99%

Glutamine reliance in cell metabolism

et al. 2020

View full text Add to dashboard Cite

As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

show abstract

“…However, to probe the mechanistic basis of these phenotypes, clonal lineages had to be established by single-cell isolation and used to reconstitute a heterogeneity model from a limited initial diversity. Fortunately, those same phenotypes were observed in a collection of 23 clonal lines, enabling the use of molecular profiling to identify vascular mimicry as a driver of CTC forming potential and asparagine bioavailability as a driver of metastasis through its impacts on EMT [7,8] The need for manual isolation of clonal lineages as an intermediate step toward the study of heterogeneous populations raises a substantial barrier to the exploration of a plurality of models and the synthesis of insights derived from them. As an example, tumour cells vary in their sensitivity to therapeutic agents, ranging from sensitive to tolerant to resistant [9].…”

Section: Introductionmentioning

confidence: 91%

SmartCodes: functionalized barcodes that enable targeted retrieval of clonal lineages from a heterogeneous population

Rebbeck

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Molecular barcoding has provided means to link genotype to phenotype, to individuate cells in single-cell analyses, to enable the tracking of evolving lineages, and to facilitate the analysis of complex mixtures containing phenotypically distinct lineages.To date, all existing approaches enable retrospective associations to be made between characteristics and the lineage harbouring them, but provide no path toward isolating or manipulating those lineages within the complex mixture. Here, we describe a strategy for creating functionalized barcodes that enable straightforward manipulation of lineages within complex populations of cells, either marking and retrieval of selected lineages, or modification of their phenotype within the population, including their elimination. These "SmartCodes" rely on a simple CRISPR-based, molecular barcode reader that can switch measurable, or selectable markers, on or off in a binary fashion. While this approach could have broad impact, we envision initial approaches to the study of tumour heterogeneity, focused on issues of tumour progression, metastasis, and drug resistance.

show abstract

Erratum: Asparagine bioavailability governs metastasis in a model of breast cancer

Abstract: This corrects the article DOI: 10.1038/nature25465.

Cited by 11 publications

References 1 publication

CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism

CRISPR/Cas9 knockout of human arylamine N-acetyltransferase 1 in MDA-MB-231 breast cancer cells suggests a role in cellular metabolism

Glutamine reliance in cell metabolism

SmartCodes: functionalized barcodes that enable targeted retrieval of clonal lineages from a heterogeneous population

Contact Info

Product

Resources

About