T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs).

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway-JCI

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast–specific deletion of Lkb1 results in fully penetrant polyposis in mice.

Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor - Nature Cell BiologyNicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.

Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response - Nature MetabolismGnanaprakasam et al. study the amino acid requirements during different phases of T cell activation and show how asparagine restriction imparts opposing effects during early and late phases of T cell maturation through an NRF2-dependent mechanism.

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate - Cell Research

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation - Cell Discovery

Identification of an alternative triglyceride biosynthesis pathway - NatureTriacylglycerols are an energy source produced in humans by DGAT1 and DGAT2, but disrupting these enzymes reveals a noncanonical pathway involving the protein DIESL (formerly TMEM68) and its regulator TMX1, which is important during lipid scarcity.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis - Nature MetabolismHere Mukherjee et al. characterize the bidirectional communication between adipose tissue and ovarian cancer cells and show that adipocytes instruct cancer cells to divert glycolytic glycerol-3-phosphate towards lipid synthesis, thus promoting metastasis.

Uridine-derived ribose fuels glucose-restricted pancreatic cancer - NatureA metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.

Increased demand for NAD+ relative to ATP drives aerobic glycolysisAerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation acr…

Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cellsProliferating cells exhibit a metabolic phenotype known as “aerobic glycolysis,” which is characterized by an elevated rate of glucose fermentation to…

Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis - Nature BiotechnologyMany diseases are characterized by shifts in cellular energy metabolism. Gohil et al. use a quantitative, nutrient-sensitized screen to identify drugs that affect the relative rates of glycolysis and mitochondrial respiration, and demonstrate the protective capacity of an approved antiemetic in models of cardiac and cerebral ischemia.

Slow TCA flux and ATP production in primary solid tumours but not metastases - NatureAs solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

A pan-cancer metabolic atlas of the tumor microenvironmentTumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we use a tumor transcriptome deconvolution approach to prof…

AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction SystemAMPK is a central regulator of metabolism and autophagy. Here we show how lysosomal damage activates AMPK. This occurs via a hitherto unrecognized sig…

Determination of glucose deficiency-induced cell death by mitochondrial ATP generation-driven proton homeostasisAbstract. Glucose is one of major nutrients and its catabolism provides energy and/or building bricks for cell proliferation. Glucose deficiency results in cell

What is cancer metabolism?The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While m…

Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms - Nature CommunicationsGlucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.

EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvationThe stress-responsive transcription factor TFEB is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. Integrative genomic analyses identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression and reveal the function of the EGR1-TFEB transcriptional axis in physiology and disease.

LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung AdenocarcinomaDifferences in the effects of LKB1 loss in human versus murine lung adenocarcinoma are attributed to differential TPI1 regulation that leads to divergent metabolic liabilities and has implications for therapeutic targeting in cancer.

Identification of metabolic networks by genetic co-essentiality analysis - Nature Reviews Molecular Cell BiologyIn this Tools of the Trade article, Benjamin Jackson (at the Finley lab) describes the use of genetic co-essentiality analysis to interrogate the assembly of metabolic networks, fuelling discovery of new aspects of metabolism.

Cancer metabolism: looking forward - Nature Reviews CancerThis Perspective discusses the main themes in cancer metabolism research that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing emerging aspects and questions that remain unanswered.

Redefining the role of AMPK in autophagy and the energy stress response - Nature CommunicationsAccording to the current understanding in the field, AMPK promotes autophagy by activating ULK1 during energy stress. Here, authors show that AMPK is indeed a negative regulator of ULK1 and it suppresses autophagy in energy depleted cells.

A non-canonical tricarboxylic acid cycle underlies cellular identity - NatureA non-canonical tricarboxylic acid cycle is required for changes in cell state.

Thrifty energy metabolism in solid tumoursTumours generate cellular energy through metabolic pathways more slowly than most healthy tissues do.

Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cellsOxygenated cancer cells excrete much of the glucose they consume as lactate, a seemingly wasteful process that has been challenging to rationalize. Here, Wang et al. demonstrate that proliferating cells prefer to oxidize glucose. Lactate excretion primarily occurs because glycolysis produces NADH faster than shuttles can transport electrons into mitochondria.

easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targetingAbstract. The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-targe

Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1-Science

Linking AMPK to organelle biogenesis

The kinase AMPK is a key sensor that helps to control energy homeostasis. Malik et al. reveal the mechanism by which AMPK controls the transcription factor TFEB to increase gene transcription and to support mitochondrial and lysosomal biogenesis. AMPK appears to act by direct phosphorylation of folliculin-interacting protein 1 (FNIP1). FNIP is part of a complex that acts as a GTP-activating protein for the GTPases RagC and RagD, which regulate the mechanistic target of rapamycin complex 1 protein kinase signaling complex on the lysosomal surface. This results in release of TFEB from the lysosome, allowing it to act at the nucleus.

The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress - Nature MetabolismMa et al. find that PHGDH, which catalyses serine metabolism in the cytoplasm, transits to the nucleus during nutrient stress, where it promotes cell growth and tumorigenesis.

Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter - Nature CommunicationsAMP activated protein kinase (AMPK) is a master regulator of cellular metabolism, but how AMPK activity is spatiotemporally regulated remains unclear. Here, Schmitt et al develop a sensitive biosensor for AMPK, which they use to uncover mechanisms for AMPK activity in the lysosome and nucleus.

AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis - Nature CommunicationsEnergy 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.

Dihydroxyacetone phosphate signals glucose availability to mTORC1 - Nature MetabolismLevels of the glycolytic intermediate metabolite dihydroxyacetone phosphate are shown to signal cellular glucose availability to the mTORC1 complex through an AMPK-independent route.

Anti-inflammatory functions of the glucocorticoid receptor require DNA bindingAbstract. The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Ge

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancerA subset of lung cancer cell lines is sensitive to activation of the transcription factor NRF2. The metabolic state of a cancer cell dictates sensitivity to NRF2, whose activation results in a NADH/NAD+ imbalance. As a result, the blockade of mitochondrial Complex I is a synthetic lethality in NRF2-activated lung cancers.

The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non–small cell lung cancerWe identify CRTC2 as a key mediator of LKB1-mutant non–small cell lung cancer.

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