Featured
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Article |
Methionine is a metabolic dependency of tumor-initiating cells
Elevated activity of the methionine cycle is essential for cancer stem cell tumorigenesis and represents a therapeutic vulnerability.
- Zhenxun Wang
- , Lian Yee Yip
- & Wai Leong Tam
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Article |
Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
Blockade of intrahepatic accumulation and function of platelets represents a potential approach to treat non-alcoholic steatohepatitis (NASH) and prevent subsequent progression to hepatocellular carcinoma
- Mohsen Malehmir
- , Dominik Pfister
- & Mathias Heikenwalder
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Article |
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Blockade of ERK signaling in KRAS-mutant pancreatic cancer increases the dependence on autophagic flux through different mechanisms and provides a rationale for combinatorial targeting with autophagy inhibitors.
- Kirsten L. Bryant
- , Clint A. Stalnecker
- & Channing J. Der
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Perspective |
The emerging link between cancer, metabolism, and circadian rhythms
Disruption of the circadian clock has been linked to cancer and alterations in cancer metabolism and this has implications for therapeutic development.
- Selma Masri
- & Paolo Sassone-Corsi
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Article |
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib
Mapping of the clonal structure of bone marrow cells in patients with acute myeloid leukemia treated with the IDH2 inhibitor enasidenib reveals heterogeneity in the cellular differentiation response and in mechanisms of relapse.
- Lynn Quek
- , Muriel D. David
- & Paresh Vyas
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Article |
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
An oncometabolite produced by tumor cells acts as a paracrine immunosuppressant dampening antitumor T cell responses in glioma.
- Lukas Bunse
- , Stefan Pusch
- & Michael Platten
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Article |
Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models
A small molecule selectively targeting the cell-surface glutamine transporter ASCT2 disrupts glutamine signaling and metabolism. This compound displays low toxicity and strong antitumor activity in preclinical in vitro and in vivo models, thus holding promise as a treatment for glutamine-dependent tumors in a clinical setting.
- Michael L Schulte
- , Allie Fu
- & H Charles Manning
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Article |
Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.
- Wilson X Mai
- , Laura Gosa
- & David A Nathanson
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Letter |
Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells
Treatment with tyrosine kinase inhibitors results in a survival benefit in patients with chronic myeloid leukemia (CML). However, relapse due to persistent leukemic stem cells (LSCs) requires additional selective targets for efficient eradication of the disease. Metabolomic analyses on patient-derived CML LSCs reveal that these have an increased dependency on oxidative metabolism that renders them sensitive to treatment with tigecycline, an FDA-approved inhibitor of mitochondrial translation. These findings uncover a new metabolic vulnerability in CML and provide a rational approach for further clinical evaluation.
- Elodie M Kuntz
- , Pablo Baquero
- & Eyal Gottlieb
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Article |
The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia
Transcriptomic and metabolic profiling reveals that the creatine kinase pathway is essential for growth of acute myeloid leukemias expressing the transcription factor EVI1.
- Nina Fenouille
- , Christopher F Bassil
- & Kimberly Stegmaier
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Letter |
Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Using a device implanted in KRAS-driven pancreatic tumors, authors demonstrate that cancer cells incorporate proteins in their microenvironment as a source of amino acids. This work provides a novel approach to study tumor metabolism that could be applied with therapeutic purposes.
- Shawn M Davidson
- , Oliver Jonas
- & Matthew G Vander Heiden
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Article |
Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome
A pharmacological screen has identified the histone methyltransferase G9a as a target to reactivate imprinted genes in a mouse model of Prader–Willi Syndrome that improves growth and survival.
- Yuna Kim
- , Hyeong-Min Lee
- & Yong-hui Jiang
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Letter |
Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth
By reducing the availability of extracellular L-cyst(e)ine, an engineered enzyme inhibits glutathione production and cripples antioxidant defenses of tumors in a variety of mouse models.
- Shira L Cramer
- , Achinto Saha
- & Everett Stone
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News & Views |
Blocking fatty acid synthesis reduces lung tumor growth in mice
Tumors often overexpress enzymes that synthesize fatty acids, but the requirement for fatty acid synthesis in tumor growth is unclear. A new fatty acid–synthesis inhibitor blunts lung tumor growth in mice, which implicates this process as a targetable liability.
- Jiyeon Kim
- & Ralph J DeBerardinis
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Article |
Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models
An allosteric inhibitor of acetyl-CoA carboxylase reveals a metabolic liability of non-small-cell lung cancer and slows tumor growth alone and in combination with chemotherapy in mouse models.
- Robert U Svensson
- , Seth J Parker
- & Reuben J Shaw
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Article |
An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
Cancer cachexia is marked by a pathological loss of fat tissue, but preventing the degradation of AMPK in this tissue helps preserve its mass in mouse models.
- Maria Rohm
- , Michaela Schäfer
- & Stephan Herzig
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Article |
CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma
Expression of HNF1A and KRT81 stratifies pancreatic ductal adenocarcinoma tumors into different subtypes, and expression of cytochrome P450 3A5 mediates basal and/or drug-induced therapy resistance in each subtype.
- Elisa M Noll
- , Christian Eisen
- & Martin R Sprick
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Article |
Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia
In NOTCH-induced T cell acute lymphoblastic leukemia, the resistance to anti-NOTCH therapy conferred by loss of the Pten tumor suppressor is linked to reversal of the effects of NOTCH inhibition on leukemic cell metabolism.
- Daniel Herranz
- , Alberto Ambesi-Impiombato
- & Adolfo A Ferrando
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News & Views |
Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia
A new study identifies recurrent mutations in the purine biosynthesis gene phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in relapsed acute lymphoblastic leukemia (ALL). This work highlights the importance of this pathway in the pathogenesis of relapse and suggests an approach to predicting and circumventing resistance in ALL.
- Charles G Mullighan
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News & Views |
A synthetic lethal approach targeting mutant isocitrate dehydrogenase in acute myeloid leukemia
Pathogenic mutations of the genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) occur in people with acute myeloid leukemia or other tumors. A new study identifies a dependence of IDH-mutated cells on the anti-apoptosis regulator BCL-2 and indicates a 'synthetic lethal' strategy for the treatment of leukemias.
- Amit Verma
- & Ulrich Steidl
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Letter |
Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
IDH1 and IDH2 mutations sensitize acute myeloid leukemia cells to the BCL-2 inhibitor ABT-199.
- Steven M Chan
- , Daniel Thomas
- & Ravindra Majeti
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Letter |
Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development
Elevated plasma levels of branched chain amino acids detected prior to pancreatic cancer diagnosis may result from whole body tissue breakdown occurring during the early stages of this disease.
- Jared R Mayers
- , Chen Wu
- & Brian M Wolpin
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Between Bedside and Bench |
The Many Faces of Sirtuins: Sirtuins and the Warburg effect
Metabolic regulators that permit adaptation to changes in caloric intake have been shown to be needed to protect from age-related disorders. Sirtuins play a crucial part in this program, impinging on not only aging but also other diseases. New findings are uncovering the multifaceted activity of sirtuins in living organisms and their effects on healthspan. In 'Bedside to Bench', Leonard Guarente discusses how different sirtuins are hindering cancer metabolism through suppression of the Warburg effect. The apparent antitumor effects of several sirtuins through their regulation of different metabolic pathways suggest therapeutic approaches to induce sirtuin function or that of downstream targets may block cancer growth. In 'Bench to Bedside', Eric Verdin peruses a few studies in different animal models showing that increased amounts of nicotinamide adenine dinucleotide (NAD), a cofactor of sirtuins, may have a positive effect in longevity and span of healthy life, or healthspan, by increasing sirtuin enzymatic activity. Whether harnessing NAD therapeutically is a potential way to extend lifespan and ameliorate diseases is still open to debate.
- Leonard Guarente
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News & Views |
BCAT1 defines gliomas by IDH status
Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901–908).
- Jared R Mayers
- & Matthew G Vander Heiden
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Article |
LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker
The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis.
- Dahu Chen
- , Yutong Sun
- & Li Ma
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Between Bedside and Bench |
Untuning the tumor metabolic machine: Targeting cancer metabolism: a bedside lesson
Several decades of scientific observations followed by years of basic and now clinical research support the notion that the metabolic power of tumor cells can provide the long-desired Achilles' heel of cancer. Yet many questions remain as to what defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act as tumor suppressors or oncogenes. In 'Bedside to Bench', Kıvanç Birsoy, David M. Sabatini and Richard Possemato discuss how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or by directly targeting the power plant of tumor cells. In 'Bench to Bedside', Regina M. Young and M. Celeste Simon peruse the complex function of a key metabolic factor that mediates the cell's response to low oxygen levels, often found in tumors. This hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments.
- Kıvanç Birsoy
- , David M Sabatini
- & Richard Possemato
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Between Bedside and Bench |
Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?
- Regina M Young
- & M Celeste Simon
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Between Bedside and Bench |
The secrets of the bone marrow niche: Metabolic priming for AML
- Rushdia Z Yusuf
- , Ying-Hua Wang
- & David T Scadden
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Letter |
Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth
Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.
- Kristin M Nieman
- , Hilary A Kenny
- & Ernst Lengyel
Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials