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| Open AccessDeleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies
Treatment failure following chimaeric antigen receptor (CAR) T cell therapy is common yet incompletely understood. In this study, the authors demonstrate that deletion of the mitochondrial negative regulator, MCJ, in CAR T cells promotes target cell killing ex vivo and augments their efficacy in an in vivo B cell leukaemia model.
- Meng-Han Wu
- , Felipe Valenca-Pereira
- & Mercedes Rincon
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Article
| Open AccessTryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis
Amino acids availability is normally a limitation for protein synthesis and can determine cancer progression and therapy response. Here, the authors show that MYC-associated cancer has a dependency on tryptophan not because of translation regulation, but Indole 3-Pyruvate synthesis.
- Niranjan Venkateswaran
- , Roy Garcia
- & Maralice Conacci-Sorrell
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessMitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC
The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.
- Nathan P. Ward
- , Sang Jun Yoon
- & Gina M. DeNicola
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessmTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism
How cells adapt to glucose starvation is still elusive. Here, Levy et al. show that the mTOR substrate 4EBP1 protects human, mouse, and yeast cells from glucose starvation and is exploited by cancer cells to promote tumorigenesis.
- Tal Levy
- , Kai Voeltzke
- & Gabriel Leprivier
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Article
| Open AccessFGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
FGFR inhibitors (FGFRi) benefit patients with FGFR2-fusion positive intrahepatic cholangiocarcinoma (ICC) but depth and duration of response is often limited. Here, the authors demonstrate that oncogenic FGFR2 signaling promotes a glycolytic phenotype, which is blocked by FGFRi, resulting in a targetable dependence on mitochondrial metabolism.
- Yuanli Zhen
- , Kai Liu
- & Nabeel Bardeesy
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Article
| Open AccessActive site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms
Here the authors show mutants of isocitrate dehydrogenase 1 (IDH1), an enzyme implicated in various cancers, have distinct catalytic and structural features that drive their ability to generate an oncometabolite.
- Matthew Mealka
- , Nicole A. Sierra
- & Christal D. Sohl
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Article
| Open AccessMitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression
The interaction between colon cancer cells and colonic epithelial cells (CECs) is critical yet not well-known. Here, the authors show that tumor extracellular vesicles mediate mitochondrial DNA transfer to CECs, initiating mitochondrial activation and RelA-induced TGFβ1 expression, leading to tumor progression.
- Bingjie Guan
- , Youdong Liu
- & Dongwang Yan
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Article
| Open AccessWild-type IDH2 is a therapeutic target for triple-negative breast cancer
Isocitrate dehydrogenase (IDH) mutations are associated with cancer development and IDH-mutant inhibitors are approved to treat IDH-mutant cancer. Here, the authors show in preclinical murine models that wild-type IDH2 is a potential therapeutic target for triple-negative breast cancer.
- Jiang-jiang Li
- , Tiantian Yu
- & Peng Huang
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Article
| Open AccessMyeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies
Myeloid derived suppressor cells (MDSC) are associated with tumourigenesis and therapy response. Here, the authors show that beta 2-adrenergic receptor activation in MDSC leads to metabolic rewiring which regulates chemotherapy response in preclinical models of blood cancer.
- Saeed Daneshmandi
- , Jee Eun Choi
- & Hemn Mohammadpour
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Article
| Open AccessPolyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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Article
| Open AccessTherapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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Article
| Open AccessLactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
| Open AccessFilament formation drives catalysis by glutaminase enzymes important in cancer progression
Mitochondrial enzymes, collectively known as glutaminase, satisfy the metabolic requirements of cancer cells. Here the authors show that glutaminases form filamentous structures necessary for their catalytic activity.
- Shi Feng
- , Cody Aplin
- & Richard A. Cerione
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Article
| Open AccessInhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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Article
| Open AccessThe transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Cancer cells adapt to changes in metabolism to ensure their survival. Here the authors show that glucose responsive transcription factor ChREBP reprograms liver cancer metabolism in part via enhancing the PI3K/AKT signaling.
- Emmanuel Benichou
- , Bolaji Seffou
- & Renaud Dentin
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Article
| Open AccessInfluence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial
MIND-DC was a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived natural dendritic cell (nDC)-based therapy in patients with stage III melanoma, showing that nDC-induced immune responses did not translate into survival benefit. Here the authors report that, despite randomization, baseline differences in fecal metagenomics and serum metabolomics profiles between treatment arms might have influenced the clinical outcome of the trial.
- Carolina Alves Costa Silva
- , Gianmarco Piccinno
- & I. Jolanda M. de Vries
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| Open AccessMetabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Article
| Open AccessUnraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses
Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.
- Seong Eun Lee
- , Seongyeol Park
- & Yea Eun Kang
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Article
| Open AccessCaloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.
- Rani Pallavi
- , Elena Gatti
- & Pier Giuseppe Pelicci
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Article
| Open AccessAKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
The metabolic switch of tumours to aerobic glycolysis can allow them to meet their increasing energetic demands. Here, the authors show that AKT1 regulates this switch through the phosphorylation of malic enzyme 2 (ME2) preventing mitochondrial translocation. In turn this pushes the cell from mitochondrial metabolism to glycolysis, promoting tumour growth.
- Taiqi Chen
- , Siyi Xie
- & Wenjing Du
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Article
| Open AccessLeukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Cancer cachexia is a systemic syndrome characterized by dramatic weight loss and decline in adipose tissue and skeletal muscle mass. Here, the authors show that overexpression of leukemia inhibitory factor (LIF), a secreted cytokine, suppresses de novo lipogenesis and induces cachexia in mice.
- Xue Yang
- , Jianming Wang
- & Wenwei Hu
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Article
| Open AccessNiacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma
Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NAD synthesis, has been proposed as a potential target for cancer therapy. Here, the authors show synthetic lethality when combining NAMPT inhibition with Niacin restriction in neuroendocrine-type cancer.
- Miyuki Nomura
- , Mai Ohuchi
- & Nobuhiro Tanuma
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Article
| Open AccessEnhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis
The underlying mechanisms driving colorectal cancer (CRC) through the serrated route are largely unknown. Here, the authors show that reduced aPKC levels increase cholesterol biosynthesis to promote aggressiveness in serrated tumours and targeting this pathway reduces tumourigenesis in preclinical models of serrated CRC.
- Yu Muta
- , Juan F. Linares
- & Jorge Moscat
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Article
| Open AccessItaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion
Itaconate is an immunomodulatory metabolite that has been reported to regulate tumorigenesis. Here, the authors show that macrophage-derived itaconate induces epigenetic-mediated CD8+ T cell exhaustion, promoting hepatocellular carcinoma development.
- Xuemei Gu
- , Haoran Wei
- & Ping Gao
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Article
| Open AccessMirabegron displays anticancer effects by globally browning adipose tissues
Targeting metabolism is currently a promising approach for cancer treatment. Here, the authors show that the beta3 agonist mirabegron inhibits tumor progression by browning adipose tissues in preclinical murine models.
- Xiaoting Sun
- , Wenhai Sui
- & Yihai Cao
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Article
| Open AccessSETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Article
| Open AccessMetabolic dependencies of metastasis-initiating cells in female breast cancer
Understanding the mechanisms associated with cancer metastasis may help control cancer progression. Here the authors investigate the metabolism of metastasis initiating cells in breast cancer and show that their metastatic ability relies on fatty acid oxidation and the oxidative tricarboxylic acid cycle, which in turn regulates acetyl-CoA generation and the acetylation of histones on EMT related genes.
- C. Megan Young
- , Laurent Beziaud
- & Joerg Huelsken
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Article
| Open AccessCyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
| Open AccessMutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth
Mutant p53 induces serine/glycine synthesis and essential amino acids intake. Under amino acid restriction, mutant p53 is stabilized and activates a transcriptional program that sustains a metabolic adaptive response promoting breast cancer cells growth
- Camilla Tombari
- , Alessandro Zannini
- & Giannino Del Sal
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Article
| Open AccessPalmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
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Article
| Open AccessPositive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice
Metabolic reprogramming is a hallmark of tumorigenesis. Here, the authors show that nuclear myosin 1 regulates mitochondrial oxidative phosphorylation via the TFAM and PGC1α transcription factors and suggest its depletion contributes to the Warburg effect during tumorigenesis.
- Tomas Venit
- , Oscar Sapkota
- & Piergiorgio Percipalle
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Article
| Open AccessDecreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia
Cancer cachexia is a multifactorial metabolic syndrome affecting a large fraction of patients with advanced cancer. Here the authors report a decrease in B vitamin-related liver enzymes in mouse models and gastric cancer patients with cachexia.
- Yasushi Kojima
- , Emi Mishiro-Sato
- & Masahiro Aoki
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| Open AccessThe lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
Ferroptosis is an iron-dependent cell death mechanism that is emerging as a target for cancer therapy. Here, the authors find that lipoprotein-associated phospholipase A2 modulates ferroptosis resistance by controlling phospholipid metabolism.
- Mihee Oh
- , Seo Young Jang
- & Eun-Woo Lee
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Article
| Open AccessFasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
The use of immune checkpoint inhibitors is associated with a wide range of side effects. Here the authors explore the use of periodic cycles of a diet that mimics fasting and see reduction in side effects caused by a range of immune checkpoint blockade antibodies in a preclinical cancer model.
- S. Cortellino
- , V. Quagliariello
- & V. D. Longo
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Article
| Open AccessAhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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Article
| Open AccessAcquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
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Article
| Open AccessCharacterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux
Metabolic reprogramming is a common indicator of the tumour microenvironment. Here the authors develop the METAflux framework to predict metabolic fluxes from single cell RNA-seq data.
- Yuefan Huang
- , Vakul Mohanty
- & Ken Chen
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Article
| Open AccessA HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Article
| Open AccessIntermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
The application of dietary methionine intervention is of particular interest in the field of cancer therapy. Here the authors show that intermittent but not sustained deprivation of methionine promotes tumor ferroptosis and improves response to checkpoint inhibitors.
- Ying Xue
- , Fujia Lu
- & Weimin Wang
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Article
| Open AccessTargeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
KRAS mutations are associated with an immunosuppressive microenvironment in patients with colorectal cancer (CRC). Here the authors show that knockout of SLC25A22, a mitochondrial glutamate carrier, reverts KRAS-mediated immunosuppression in preclinical CRC models, by suppressing CXCL1 production and impairing MDSC recruitment.
- Qiming Zhou
- , Yao Peng
- & Chi Chun Wong
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Article
| Open AccessA bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses
Metabolic pressure, in particular the lack of methionine availability, on tumor-infiltrating CD8 + T cells is associated with T cell dysfunction. Since tumor cells rely on SLC43A2 for methionine uptake, here the authors design a nanoplatform for CRISPR/Cas9 mediated silencing of SLC43A2 and STING activation, restoring anti-tumor T cell immune responses.
- Ying Huang
- , Geng Qin
- & Xiaogang Qu
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Article
| Open AccessOncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma
Glioblastoma (GBM) cells are metabolically dependent on exogenous cholesterol uptake and targeting cholesterol metabolism has been proposed as a therapeutic option for GBM. Here the authors show that cholesterol promotes phagocytic dysfunction in tumor associated macrophages and they develop an Apo-A1 armed oncolytic adenovirus restoring anti-tumor immunity in GBM preclinical models.
- Wang Shiqun
- , Yan Wei
- & Wei Jiwu
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Article
| Open AccessOxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers
Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models.
- Rania El-Botty
- , Ludivine Morriset
- & Elisabetta Marangoni
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Article
| Open AccessACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis
Diagnostic markers and therapeutic targets for gastric cancer are in urgent need. Here, the authors 2 find elevated expression of ACTL6A in gastric cancer promotes glutathione synthesis by regulating 3 GCLC expression to suppress ferroptosis.
- Ziqing Yang
- , Shaomin Zou
- & Lekun Fang
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Article
| Open AccessIncreased glucose availability sensitizes pancreatic cancer to chemotherapy
Response to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) is often limited. Here, the authors report improved response to chemotherapy in PDAC patients with hyperglycaemia and investigate the underlying mechanism via glucose-mediated disruption of redox metabolism
- Ali Vaziri-Gohar
- , Jonathan J. Hue
- & Jordan M. Winter
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Article
| Open AccessSLC7A11 expression level dictates differential responses to oxidative stress in cancer cells
The cystine transporter SLC7A11 protects cancer cells from oxidative stress by supporting glutathione synthesis. Here, the authors show that the expression level of SLC7A11 leads to different outcomes depending on context, so high expression promotes primary tumour growth but promotes disulfide stress under oxidative stress conditions and impairs metastasis.
- Yuelong Yan
- , Hongqi Teng
- & Boyi Gan