Featured
-
-
Article
| Open AccessPHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma
The role of protein arginine methylation in serine metabolism of cancer cells in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors show that phosphoglycerate dehydrogenase (PHGDH) is activated by PRMT1-mediated R236 methylation, promoting serine synthesis, redox homeostasis and HCC growth.
- Kui Wang
- , Li Luo
- & Canhua Huang
-
Article
| Open AccessGlycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
KRAS is a small GTPase that regulates cell proliferation. Here, the authors show that a subset of cell surface glycosphingolipids regulate KRAS plasma membrane localization by modulating inner leaflet lipid composition, uncovering a requirement for KRAS oncogenesis that may have therapeutic potential.
- Junchen Liu
- , Ransome van der Hoeven
- & John F. Hancock
-
Article
| Open AccessSmarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma
Clinical management of pancreatic cancer remains challenging. Here, the authors suggest SMARCD3 as a potential epigenetic dependency establishing the metabolic landscape in aggressive pancreatic cancer cells and as a potential therapeutic target in pancreatic cancer.
- L. Paige Ferguson
- , Jovylyn Gatchalian
- & Tannishtha Reya
-
Article
| Open AccessDynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression
Primary and metastatic tumours have different metabolic phenotypes due to changes in nutrient availability. Here the authors perform multi-omic analyses of primary and metastatic renal cancer cells grown in a physiological medium and show that the reprogramming of the branched-chain amino acid catabolism and urea cycle through re-expression of ASS1 allows metabolic flexibility during renal cancer progression.
- Marco Sciacovelli
- , Aurelien Dugourd
- & Christian Frezza
-
Article
| Open AccessAMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis
Energy stress activates AMPK leading to metabolic plasticity and therapy resistance in cancer. Here, the authors show that AMPK activation decreases Prospero-related homeobox 1 (PROX1) levels impairing branched amino acid metabolism and tumourigenesis in liver and lung cancer models.
- Yanan Wang
- , Mengjun Luo
- & Yanfeng Liu
-
Article
| Open AccessLong noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer
While aromatase inhibitors (AI) are an effective treatment for patients with estrogen receptor positive breast cancer, resistance presents a major obstacle. Here, the authors identify DIO3OS, a long noncoding RNA, as a driver of AI-resistance in breast cancer through the enhancement of aerobic glycolysis.
- Xueman Chen
- , Rong Luo
- & Erwei Song
-
Article
| Open AccessBRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy
Targeted therapeutic options for NRAS-mutant melanoma are limited. Here, the authors show that under metabolic stress NRAS-mutant melanoma cells activate a BRAF-dependent glycolysis pathway for survival, leading to improve efficacy of sorafenib when combined with glycolysis inhibitors.
- Kimberley McGrail
- , Paula Granado-Martínez
- & Juan A. Recio
-
Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
-
Article
| Open AccessMetabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion
Chemo-resistance and immune evasion are major challenges in osteosarcoma treatment. Here the authors show that doxorubicin promotes IL-18 secretion by tumor associated macrophages inducing LAT2-dependent CD47 upregulation in osteosarcoma cells, suggesting LAT2 inhibition as a therapeutic option in combination with doxorubicin.
- Zenan Wang
- , Binghao Li
- & Zhaoming Ye
-
Article
| Open AccessTumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression
Methylmalonic acid (MMA) is increased in aging as well as produced by advanced tumors, and can drive pro-aggressive changes in these tumor cells. Here, the authors show that MMA can also act on fibroblasts in the tumor microenvironment, recruiting and activating them to further support tumor progression.
- Zhongchi Li
- , Vivien Low
- & John Blenis
-
Article
| Open AccessSirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability
Sirtuin 5 (SIRT5) has been associated to colorectal cancer and metabolic regulation. Here, the authors show that SIRT5 silencing reduces nucleotide availability leading to DNA damage and tumor suppression in colorectal cancer models.
- Hao-Lian Wang
- , Yan Chen
- & Jing-Yuan Fang
-
Article
| Open AccessATF4-dependent fructolysis fuels growth of glioblastoma multiforme
Excessive consumption of fructose contributes to cancer development, but the underlying mechanisms are poorly understood. Here, the authors show that glucose deprivation induces fructolysis through selective activation of ATF4 translation, thereby supporting malignant progression of human glioblastoma.
- Chao Chen
- , Zhenxing Zhang
- & Xinjian Li
-
Article
| Open AccessCD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis
Macrophage-mediated immune suppression contributes to poor outcome in liver metastasis. Here the authors show that CD36-expressing metastasis associated macrophages engulf tumor cell-derived extracellular vesicles enriched in long-chain fatty acids, acquiring a pro-tumorigenic phenotype in a preclinical liver metastasis model.
- Ping Yang
- , Hong Qin
- & Xiong Z. Ruan
-
Article
| Open AccessUSP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer
IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.
- Dongni Shi
- , Xianqiu Wu
- & Wenting Liao
-
Article
| Open AccessSingle cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.
- Vincent Geldhof
- , Laura P. M. H. de Rooij
- & Peter Carmeliet
-
Article
| Open AccessInhibition of UBA6 by inosine augments tumour immunogenicity and responses
The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.
- Lei Zhang
- , Li Jiang
- & Baokun He
-
Article
| Open AccessFatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37
Tetraspanin CD37 deficiency has been reported as a prognostic marker for aggressive B-cell lymphoma. Here, the authors show that CD37 interacts with the fatty acid transporter 1 to inhibit palmitate uptake and its deficiency leads to increased fatty acid metabolism which promotes tumorigenesis in B-cell lymphoma.
- Rens Peeters
- , Jorge Cuenca-Escalona
- & Annemiek B. van Spriel
-
Article
| Open AccessLactate increases stemness of CD8 + T cells to augment anti-tumor immunity
Lactic acid from glycolytic metabolism of cancer cells has been associated with immune suppressive functions. Here authors show that lactate, when depart from the acidic protons, inhibits histone deacetylases in CD8 + T cells, which turns them into potent anti-tumour immune cells.
- Qiang Feng
- , Zhida Liu
- & Jinming Gao
-
Article
| Open AccessSingle cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma
The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.
- Shannon Coy
- , Shu Wang
- & Sandro Santagata
-
Article
| Open AccessMYC sensitises cells to apoptosis by driving energetic demand
MYC activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.
- Joy Edwards-Hicks
- , Huizhong Su
- & Andrew J. Finch
-
Article
| Open AccessBlocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
- Andre Lima Queiroz
- , Ezequiel Dantas
- & Marcus D. Goncalves
-
Article
| Open AccessMetabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells
Metabolic reprogramming is associated with cancer initiation, progression and resistance to therapy. Here, the authors show that metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation is associated with cancer-cell platinum-based chemotherapy resistance.
- Yuying Tan
- , Junjie Li
- & Ji-Xin Cheng
-
Article
| Open AccessSerine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Metabolic reprogramming is associated with cancer development and therapy resistance. Here, the authors show that downregulation of the serine biosynthesis enzyme PHGDH in a fraction of patients is associated with relapse in platinum-treated ovarian cancers and to NAD+ and PARP activity upregulation.
- Tom Van Nyen
- , Mélanie Planque
- & Frédéric Amant
-
Article
| Open AccessTargeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer
Mutant KRAS (KM) is associated with poor prognosis in lung cancer and reported to promote lipid metabolism. Here, the authors show that fatty acid synthesis, which provides lipids to repair oxidized phospholipids through the FASN-Lands cycle axis, is a specific vulnerability for KM lung cancer.
- Caterina Bartolacci
- , Cristina Andreani
- & Pier Paolo Scaglioni
-
Article
| Open AccessBlocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance
The bone tumour microenvironment plays an essential role in multiple myeloma (MM) development. Here, the authors show that bone collagen degradation provides glycine to support MM progression through glutathione and purine synthesis.
- Jiliang Xia
- , Jingyu Zhang
- & Wen Zhou
-
Article
| Open AccessThe cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer
Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.
- Chi Chun Wong
- , Jian-Lin Wu
- & Jun Yu
-
Article
| Open AccessMitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression
Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.
- Xinyuan Lei
- , Hsinyu Lin
- & Jinsong Li
-
Article
| Open AccessMYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma
Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models.
- Ling Tao
- , Mahmoud A. Mohammad
- & Eveline Barbieri
-
Article
| Open AccessFUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion
Fragmented mitochondria are a frequent hallmark of cancer, but the cause and consequence are less clear. The authors demonstrate that elevated FUNDC2 causes mitochondrial fragmentation through inhibition of MFN1 in hepatocellular carcinoma and that knockdown of FUNDC2 inhibits liver tumorigenesis in mice.
- Shuaifeng Li
- , Shixun Han
- & Bin Zhao
-
Article
| Open AccessRemote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase
The presence of cancer can induce systemic disruption of the host homeostasis. Here, the authors show that different solid tumours remotely increase hepatic nicotinamide-Nmethyltransferase disrupting the host urea cycle metabolism in the liver.
- Rin Mizuno
- , Hiroaki Hojo
- & Shinpei Kawaoka
-
Article
| Open AccessNeddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells
Neddylation inhibition has been reported as a therapy for cancer. Here, the authors show that neddylation inhibition increases glutamine metabolism by stabilizing glutamine transporter ASCT2, therefore targeting ASCT2 improves the anti-cancer effect of neddylation inhibitors.
- Qiyin Zhou
- , Wenyu Lin
- & Yi Sun
-
Article
| Open AccessInhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.
- Natalia Baran
- , Alessia Lodi
- & Marina Konopleva
-
Article
| Open AccessMitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis
Chemotherapeutic antifolates, such as methotrexate (MTX), impair cancer cell proliferation by inhibiting nucleotide synthesis. Here, the authors show that MTX sustains an autarkic mitochondrial one-carbon metabolism leading to serine synthesis to promote cancer cell migration and metastasis.
- Nicole Kiweler
- , Catherine Delbrouck
- & Johannes Meiser
-
Article
| Open AccessRapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ
Pancreatic intraepithelial neoplasia (PanIN) can develop into pancreatic ductal adenocarcinoma (PDAC), however, the factors which determine how this occurs are unknown. Here, the authors illustrate the role of PPARδ in the upregulation of CCL2, resulting in an immunosuppressive microenvironment, and driving the progression of PanIN to PDAC.
- Yi Liu
- , Yasunori Deguchi
- & Imad Shureiqi
-
Article
| Open AccessGermline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.
- Mahmoud A. Bassal
- , Saumya E. Samaraweera
- & Richard J. D’Andrea
-
Article
| Open AccessGut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate
The role of gut microbiota in acute myeloid leukaemia (AML) remains unclear. Here, the authors show disordered gut microbiota and reduced butyrate cause intestinal barrier damage in AML mice, with increased plasma LPS that accelerates AML progression.
- Ruiqing Wang
- , Xinyu Yang
- & Daoxin Ma
-
Article
| Open AccessRegulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer
IRE1α cleaves several mRNAs upon accumulation of misfolded proteins. Here the authors show that active IRE1α cleaves DGAT2 mRNA encoding the rate-limiting enzyme in the synthesis of triacylglycerols, suggesting a role of IRE1α in reprogramming lipid metabolism in cancer cells.
- Aitor Almanza
- , Katarzyna Mnich
- & Afshin Samali
-
Article
| Open AccessUSP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma
Different deubiquitinases are associated to cancer development. Here, the authors show that PPARgamma is stabilized by USP22-mediated deubiquitination leading to lipid accumulation and promoting hepatocellular carcinoma.
- Zhen Ning
- , Xin Guo
- & Hai-long Piao
-
Article
| Open AccessInhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
Inhibition of specific metabolic pathways often drives metabolic adaptation. Here, the authors show that FLT3-ITD + acute myeloid leukemia cells are OXPHOS-driven, and inhibition of complex II activity results in increased lactate influx to drive respiration, which creates a targetable vulnerability.
- Ayşegül Erdem
- , Silvia Marin
- & Jan Jacob Schuringa
-
Article
| Open AccessUSP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity.
- Jessica K. Nelson
- , May Zaw Thin
- & Axel Behrens
-
Article
| Open AccessMTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
- Omar Alhalabi
- , Jianfeng Chen
- & Jianjun Gao
-
Article
| Open AccessPhase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia
Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.
- Rebecca Anderson
- , Lance D. Miller
- & Timothy S. Pardee
-
Article
| Open AccessA non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
Metabolic reprogramming upon SIRT6 loss induces tumour formation in the intestine but the mechanism is unclear. Here, the authors show that loss of SIRT6 leads to the expansion of epithelial cells with high pyruvate dehydrogenase kinase activity resulting in enhanced stem cell activity and tumour-initiating potential
- Carlos Sebastian
- , Christina Ferrer
- & Raul Mostoslavsky
-
Article
| Open AccessIndisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.
- Anke Nijhuis
- , Arti Sikka
- & Hector C. Keun
-
Article
| Open AccessAdaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma
Different adaptive mechanisms have been reported to reduce the efficacy of mutant BRAF inhibition in melanoma. Here, the authors show BRAF inhibition induces the translational regulation of metabolic genes leading to acquired therapy resistance.
- Lorey K. Smith
- , Tiffany Parmenter
- & Grant A. McArthur
-
Article
| Open AccessThe Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia
Acute myeloid leukemia (AML) is genetically a very heterogeneous disease. Here, Erdem et al. uncover heterogeneity in the metabolic landscape of AML and identify Pyruvate dehydrogenase kinase 1 (PDK1) as a targetable determinant of different metabolic states in distinct subtypes of AML.
- Ayşegül Erdem
- , Silvia Marin
- & Jan Jacob Schuringa
-
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