Featured
-
-
Article
| Open AccessHypoxia-induced macropinocytosis represents a metabolic route for liver cancer
Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
- Misty Shuo Zhang
- , Jane Di Cui
- & Carmen Chak-Lui Wong
-
Article
| Open AccessA non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis
Hexokinase 2 expression is markedly induced in cancer cells and contributes to cancer cell metabolism. Here, the authors show that hexokinase 2 can contribute to the metastatic spread of cancer cells independently of its glycolytic function via inhibiting the activity of GSK3β, which in turn elevates the protein levels of the EMT transcription factor SNAIL.
- Catherine S. Blaha
- , Gopalakrishnan Ramakrishnan
- & Nissim Hay
-
Article
| Open AccessCopy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis
Copy number alterations are pivotal genetic events in triple-negative breast cancer. Here the authors show the amplification of ENSA at the 1q21.3 region promotes the progression of TNBC via up-regulation of cholesterol biosynthesis.
- Yi-Yu Chen
- , Jing-Yu Ge
- & Ke-Da Yu
-
Article
| Open AccessEndogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity
Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products.
- Carla Umansky
- , Agustín E. Morellato
- & Lucas B. Pontel
-
Article
| Open AccessHyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer
Your paper will be accompanied by the following editor’s summary. Please let us know if there are any inaccuracies: ‘Hyperpolarised ¹³C-MRI is used to image cancer metabolism. Here the authors use this technique in prostate cancer and show that it can differentiate distinct disease states.
- Nikita Sushentsev
- , Mary A. McLean
- & Ferdia A. Gallagher
-
Article
| Open AccessC/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer
Obesity is linked to cancer risk in post-menopausal breast cancer. At the molecular level this is governed by cellular adaption to palmitic acid through epigenetic activation of a C/EBPB-dependent transcriptional network that drives tumor formation.
- Xiao-Zheng Liu
- , Anastasiia Rulina
- & Nils Halberg
-
Article
| Open AccessCopper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis
Copper depletion has been reported to improve survival in patients with triple negative breast cancer (TNBC) but the underlying mechanisms are not completely understood. Here, the authors show that copper chelation reduces mitochondrial oxidative phosphorylation leading to decreased TNBC metastasis.
- Divya Ramchandani
- , Mirela Berisa
- & Vivek Mittal
-
Article
| Open AccessMetabolic drug survey highlights cancer cell dependencies and vulnerabilities
Metabolic reprogramming contributes to cancer development and progression. Here, the authors show the utility of a metabolic drug library to uncover metabolic vulnerabilities and obtain functional insights into myeloid leukemia biology.
- Tea Pemovska
- , Johannes W. Bigenzahn
- & Giulio Superti-Furga
-
Article
| Open AccessDiscovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells
CRISPR-based knockout screens in cancer cells have suggested the existence of proliferation suppressor genes (PSG). Here, the authors develop an approach to systematically identify them, and reveal a PSG module involved in fatty acid synthesis and tumour suppression in acute myeloid leukemia cell lines.
- W. Frank Lenoir
- , Micaela Morgado
- & Traver Hart
-
Article
| Open AccessEvolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma
Metabolic reprogramming occurs during tumor progression. Here the authors decipher metabolic trajectories from preneoplasia to lung adenocarcinoma in tumor samples and identify plasma metabolites as potential predictive biomarkers for early detection.
- Meng Nie
- , Ke Yao
- & Zeping Hu
-
Article
| Open AccessN1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism
Metabolic adaptation has been reported to promote cancer, yet the underlying mechanisms are not clear. Here, the authors show that m1A methylation in tRNA regulates cholesterol metabolism in liver cancer stem cells and m1A inhibition decreases tumourigenesis in preclinical models of hepatocellular carcinoma.
- Yanying Wang
- , Jing Wang
- & Zusen Fan
-
Article
| Open AccessThe impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells
Cancer cells in culture are often grown in media conditions containing unphysiological metabolite levels. Here, the authors grow cells under physiological metabolite levels to further understand the reliance of cells on serine and find that when grown under these conditions the cells are less sensitive to serine withdrawal.
- Marc Hennequart
- , Christiaan F. Labuschagne
- & Karen H. Vousden
-
Article
| Open AccessHexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities
Pericyte-endothelial cells interaction defines tumor vasculature and has implications in tumorigenesis development and therapy efficacy. Here, the authors show that hexokinase 2- driven glycolysis activates ROCK1-MLC2 mediated contractility in pericytes leading to tumor blood vessel abnormality.
- Ya-Ming Meng
- , Xue Jiang
- & Ping-Pui Wong
-
Article
| Open AccessDHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis
The glucose transporter GLUT1 is upregulated in multiple cancers and may contribute to tumour progression, but the underlying mechanisms are poorly understood. Here, the authors show that DHHC9-mediated GLUT1 palmitoylation at Cys207 is crucial for plasma membrane localisation of GLUT1 and for tumourigenesis in glioblastoma cells.
- Zhenxing Zhang
- , Xin Li
- & Xinjian Li
-
Article
| Open AccessAurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma
Glioblastoma patients are treated with Aurora kinase A (AURKA) inhibitors but resistance can occur. Here, the authors show that AURKA inhibition induces metabolic reprogramming, which leads to increased mitochondrial activity and inhibition of oxidative metabolism sensitizes glioblastoma cells to AURKA inhibition.
- Trang T. T. Nguyen
- , Enyuan Shang
- & Markus D. Siegelin
-
Article
| Open AccessDysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer
High cholesterol has been associated with increased risk of cancer but the underlying mechanism is not completely understood. Here, the authors show that a cholesterol metabolite induces metabolic reprogramming that generates ferroptosis-resistant cancer cells leading to increased tumour growth and metastasis.
- Wen Liu
- , Binita Chakraborty
- & Donald P. McDonnell
-
Article
| Open AccessGOT1 inhibition promotes pancreatic cancer cell death by ferroptosis
The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.
- Daniel M. Kremer
- , Barbara S. Nelson
- & Costas A. Lyssiotis
-
Comment
| Open AccessMultifaceted mechanisms mediating cystine starvation-induced ferroptosis
The cyst(e)ine/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis is the most frequently targeted pathway to trigger the ferroptosis cascade and suppress tumor growth. Two recent studies present additional mechanisms underlying cystine starvation-induced ferroptosis apart from impaired GSH synthesis.
- Zhennan Shi
- , Nathchar Naowarojna
- & Yilong Zou
-
Article
| Open AccessHomozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine
The metabolite methylthioadenosine (MTA) inhibits PRMT5. Therefore, MTA accumulation due to MTA phosphorylase (MTAP) deletion has been proposed as a vulnerability for PRMT5-targeted therapy in cancer. Here, the authors show that MTA does not accumulate in MTAP-deficient cancer cells but is secreted and metabolized by MTAP-intact cells in the tumour microenvironment.
- Yasaman Barekatain
- , Jeffrey J. Ackroyd
- & Florian L. Muller
-
Article
| Open AccessmTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis
An increase in glycine decarboxylase (GLDC) activity, a key enzyme for glycine catabolism, has been associated to tumourigenesis. Here, the authors show that mTORC1 activation induces GLDC deacetylation which impairs its ubiquitin-associated degradation leading to increased GLDC activity and tumourigenesis.
- Rui Liu
- , Lin-Wen Zeng
- & Shu Li
-
Article
| Open AccessLINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling
The implications of long intergenic non-coding RNAs (lincRNAs) on cancer metabolism is unclear. Here, the authors identify that LINC00842 binds to PGC-1α and prevents PGC-1α from deacetylation by SIRT1, resulting in a metabolic reprogramming in pancreatic cancer cells.
- Xudong Huang
- , Ling Pan
- & Jian Zheng
-
Article
| Open AccessiPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4
p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.
- Delin Chen
- , Bo Chu
- & Wei Gu
-
Article
| Open AccessSTAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer
Complex I inhibition induces oxidative stress leading to cancer cell cytotoxicity. Here, the authors show, in breast cancer models, that inflammatory mediators can potentiate complex I inhibitor phenformin cytotoxicity through STAT1-mediated downregulation of the reactive oxygen species scavenger NQO1.
- Stephanie P. Totten
- , Young Kyuen Im
- & Josie Ursini-Siegel
-
Article
| Open AccessModel-based analysis uncovers mutations altering autophagy selectivity in human cancer
Although autophagy has been linked to tumourigenesis, it is unclear how genomic alterations affect autophagy selectivity in tumours. Here, the authors establish a pipeline that integrates computational and experimental approaches to show that altered autophagy selectivity is frequent in cancer cells and link glycogen autophagy with tumourigenesis.
- Zhu Han
- , Weizhi Zhang
- & Da Jia
-
Article
| Open AccessMitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance
Drug efflux through ABC transporters is a common mechanism leading to chemoresistance in cancer. Here, the authors show that mitochondrial respiration provides ATP to allow ABC transporters activity so mitochondrial respiration inhibition overcomes chemoresistance in preclinical cancer models.
- Emily L. Giddings
- , Devin P. Champagne
- & Mercedes Rincon
-
Article
| Open AccessIntegration of machine learning and genome-scale metabolic modeling identifies multi-omics biomarkers for radiation resistance
Personalized prediction of tumor radiosensitivity would facilitate development of precision medicine workflows for cancer treatment. Here, the authors integrate machine learning and genome-scale metabolic modeling approaches to identify multi-omics biomarkers predictive of radiation response.
- Joshua E. Lewis
- & Melissa L. Kemp
-
Article
| Open AccessArginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells
Alterations in metabolism and amino acid usage are common in cancer cells. Here, the authors show in prostate cancer cells that arginine globally upregulates nuclear-encoded oxidative phosphorylation genes by altering histone acetylation and retaining TEAD4 in the nucleus to transactivate genes.
- Chia-Lin Chen
- , Sheng-Chieh Hsu
- & Hsing-Jien Kung
-
Article
| Open AccessNaturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor
Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.
- Zizheng Zou
- , Xiyuan Hu
- & Zhiyong Luo
-
Article
| Open AccessInositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation
BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1High/CHD7Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.
- Sara Badodi
- , Nicola Pomella
- & Silvia Marino
-
Article
| Open AccessLipocalin 2 mediates appetite suppression during pancreatic cancer cachexia
Lipocalin 2 (LCN2) has been recently identified as an endogenous regulator of appetite. Here, using pancreatic cancer as a model of cachexia, the authors demonstrate that LCN2 is a critical mediator of cancer-associated anorexia and may be therapeutically targeted to improve patient outcomes.
- Brennan Olson
- , Xinxia Zhu
- & Daniel L. Marks
-
Article
| Open AccessThe folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation
Metabolites have been reported not only to support the highly-demanding energetic needs of cancer cells but also as signalling regulators. Here, the authors show that the activity of the folate cycle enzyme MTHFD2 stimulates PD-L1 expression impairing T cell-mediated cytotoxicity and promoting tumourigenesis.
- Man Shang
- , Huijie Yang
- & Ting Wang
-
Article
| Open AccessThe oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer
Adipogenesis associated Mth938 Domain Containing gene (AAMDC) is frequently amplified in the IntClus2 subgroup of ER + breast cancer. Here, the authors show that AAMDC drives tumourigenesis through activating PI3K-AKT-mTOR pathway for metabolic reprogramming.
- Emily Golden
- , Rabab Rashwan
- & Pilar Blancafort
-
Article
| Open AccessCitrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation
Pyruvate kinase M2 (PKM2) activity is regulated by the availability of metabolic intermediates for nucleotide and amino acid synthesis. Here, the authors show that PKM2 citrullination by PADI1 and PADI3 lowers its sensitivity to metabolic inhibitors leading to increased glycolysis and reduced cancer cell proliferation.
- Sébastien Coassolo
- , Guillaume Davidson
- & Irwin Davidson
-
Article
| Open AccessTumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma
Intratumoral CD8+ T cells commonly display a dysfunctional state, however it remains unclear whether tumor cell metabolism actively promotes T-cell exhaustion. Here, the authors show that the tumor methionine recycling pathway has a central role in promoting T-cell dysfunction in hepatocellular carcinoma, contributing to tumor immune evasion.
- Man Hsin Hung
- , Joo Sang Lee
- & Xin Wei Wang
-
Article
| Open AccessThe HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis
HIF1alpha is reported to drive tumourigenesis through activating glycolysis. Here, the authors show that HIFAL, the HIF1alpha antisense long non-coding RNA, and HIF1alpha form a positive feed-forward loop which is essential for HIF1a-mediated metabolic reprogramming and oncogenic role.
- Fang Zheng
- , Jianing Chen
- & Erwei Song
-
Article
| Open AccessRNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation
CASTOR1 is an arginine sensor that inhibits mTORC1 activation, for which this pathway is frequently dysregulated in cancers. Here the authors show that AKT and E3 ubiquitin ligase RNF167 mediate CASTOR1 phosphorylation and degradation to activate mTORC1 and promote tumorigenesis.
- Tingting Li
- , Xian Wang
- & Shou-Jiang Gao
-
Article
| Open AccessIDH1 mutations induce organelle defects via dysregulated phospholipids
The understanding of altered lipid metabolism by isocitrate dehydrogenase 1 (IDH1) mutations in gliomas at a compartment-specific level is limited. Here, the authors use Raman spectroscopy to monitor organelle-specific metabolic changes and report that IDH1 mutations induce phospholipid imbalances which lead to ER and Golgi dilation.
- Adrian Lita
- , Artem Pliss
- & Mioara Larion
-
Article
| Open AccessSerine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy
Dietary serine and glycine starvation has emerged as a potential therapy for cancer. Here, the authors show that inhibition of PHGDH, which mediates the first step in the serine synthesis pathway, improves the therapeutic efficacy of serine depletion diet in mouse xenograft models.
- Mylène Tajan
- , Marc Hennequart
- & Karen H. Vousden
-
Article
| Open AccessNon-invasive assessment of telomere maintenance mechanisms in brain tumors
Telomerase expression and the alternative lengthening of telomeres pathway are hallmarks of cancer. Here, the authors show that, in primary brain tumors, these features are correlated with metabolic signatures detectable by metabolic imaging, suggesting that they can be used to non-invasively monitor telomere maintenance in brain tumours.
- Pavithra Viswanath
- , Georgios Batsios
- & Sabrina M. Ronen
-
Article
| Open AccessProto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy
Altered lipid metabolism has been associated with tumour malignancy, but underlying mechanisms are not clear. Here the authors show that proto-oncogene Src interacts and phosphorylates metabolic enzyme phosphatidic acid phosphatase LPIN1 (lipin-1) to promote growth and metastasis in breast cancer.
- Lintao Song
- , Zhihua Liu
- & Sheng-Cai Lin
-
Article
| Open AccessPINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth
Proline metabolism is crucial to tumor proliferation. Here, the authors show PINCH-1 deficiency inhibited proline synthesis by promoting mitochondrial fragmentation via DRP1, downregulating PYCR1 expression and reducing cell proliferation in vitro and in vivo.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
-
Article
| Open AccessRaman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells
Single-cell metabolomics can offer deep insights into the metabolic reprogramming that accompanies disease states. Here, the authors use Raman spectro-microscopy for non-invasive metabolite analysis and identification of druggable metabolic susceptibilities in single live melanoma cells.
- Jiajun Du
- , Yapeng Su
- & Lu Wei
-
Article
| Open AccessmTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability
mTORC1 is a key mediator of drug resistance and also regulates autophagy. In this study, the authors demonstrate that cancer cells with acquired drug resistance exibit metabolic vulnerabilities mediated by high levels of mTORC1 and the consequent inhibition of autophagy.
- Niklas Gremke
- , Pierfrancesco Polo
- & Thorsten Stiewe
-
Article
| Open AccessSystemic muscle wasting and coordinated tumour response drive tumourigenesis
Cancer is a systemic disease that associates with host metabolic changes. Here, the authors show using Drosophila, that tumours exploit extracellular proline in response to muscle wasting, indicating that tumours induce muscle wasting as a nutrient-scavenging programme to drive tumourigenesis.
- Holly Newton
- , Yi-Fang Wang
- & Susumu Hirabayashi
-
Comment
| Open AccessFasting-mimicking diet plus chemotherapy in breast cancer treatment
A clinical trial published in Nature Communications examined the effect of fasting-mimicking diet (FMD) during chemotherapy in breast cancer patients. The overall negative study results highlight the need for ameliorating future trial design and investigating alternative FMD-based therapeutic combinations.
- Claudio Vernieri
- , Francesca Ligorio
- & Filippo de Braud
-
Article
| Open AccessOSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation
The suppression of the receptor for oncostatin M (OSMR) can prevent glioblastoma cell growth. Here, the authors demonstrate a role for OSMR in modulating glioma stem cell respiration and its impact on resistance to ionizing radiation.
- Ahmad Sharanek
- , Audrey Burban
- & Arezu Jahani-Asl
-
Article
| Open AccessPancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis
Distant metastases from pancreatic cancer patients were previously reported by the authors to be dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Here the authors report a novel metabolic adaptation that that stably activates PGD to reprogram metastatic chromatin.
- Matthew E. Bechard
- , Rana Smalling
- & Oliver G. McDonald
-
Article
| Open AccessTMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation
TMBIM6, a member of the transmembrane BI-1 motif-containing family of proteins, is overexpressed in many cancer types. Here, the authors show that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and identify an antagonist of TMBIM6 with anti-tumor properties.
- Hyun-Kyoung Kim
- , Kashi Raj Bhattarai
- & Han-Jung Chae
-
Article
| Open AccessHNF4α regulates sulfur amino acid metabolism and confers sensitivity to methionine restriction in liver cancer
The molecular determinants of differential responses of different cancer cells to methionine restriction are poorly understood. Here the authors show that hepatocyte nuclear factor 4α regulates sulfur amino acid metabolism and dictates the sensitivity of liver cancer to this dietary manipulation.
- Qing Xu
- , Yuanyuan Li
- & Xiaoling Li