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Metabolic reprogramming promotes neural crest migration via Yap/Tead signaling

ABSTRACT: The Warburg effect is one of the metabolic hallmarks of cancer cells, characterized by enhanced glycolysis even under aerobic conditions. While this physiological adaptation is associated with metastatic behavior, we still have a superficial understanding of how it affects cell motility in development and disease. Here we report that the neural crest, a migratory stem cell population in vertebrate embryos, undergoes an extensive metabolic remodeling to engage in aerobic glycolysis prior to delamination. This increase in glycolytic flux promotes Yap/Tead signaling, which directly activates the expression of a set of transcription factors to drive epithelial-to-mesenchymal transition. Our results demonstrate how shifts in carbon metabolism can trigger the gene regulatory circuits that control complex cell behaviors. Our findings also support the hypothesis that the Warburg effect is a tightly regulated developmental mechanism that is anomalously reactivated during tumorigenesis and metastasis.

ORGANISM(S): Gallus gallus

PROVIDER: GSE142101 | GEO | 2020/03/30

REPOSITORIES: GEO

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Mitochondrial ATP generation is more proteome efficient than glycolysis (M. musculus)

Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

2024-04-25 | PXD048041 | Pride

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Expression data from Drosophila melanogaster err mutant animals vs. wild type animals at a mid-second instar larval time

Project description:Cancer cells utilize a unique form of aerobic glycolysis, called the Warburg effect, to efficiently produce the macromolecules required for proliferation. Here we show that a metabolic program related to the Warburg effect is used during normal Drosophila development and regulated by the fly ortholog of the Estrogen-Related Receptor (ERR) family of nuclear receptors. dERR null mutants die as second instar larvae with abnormally low ATP levels, diminished triacylglyceride stores, and elevated levels of circulating sugars. Metabolomic profiling revealed that the pathways affected in these mutants correspond to those used in the Warburg effect. The expression of active dERR protein in mid-embryogenesis triggers a coordinate switch in gene expression that drives a metabolic program supporting the dramatic growth that occurs during larval development. This study suggests that mammalian ERR family members may promote cancer by directing a metabolic state that supports proliferation. Drosophila larvae were staged at a mid-second instar time point and hand sorted for developmental progression. Individual pools of isogenic animals were collected for each replicate. Three replcates were assayed for each genotype. The two genotypes assayed were a control wild type strain (w1118) and a transheteroallelic combination of err mutant alleles (err1/err2). Labled RNA was then hybridized onto Affymetrix microarrays.

2011-02-02 | E-GEOD-23336 | biostudies-arrayexpress

Starving advanced prostate cancer cells by pharmacological gluose deprivation with a resveratrol trimer trans-Gnetin H [PDX]

Project description:Prostate cancer is a unique disease from a metabolic perspective. Early stage localized prostate cancer does not typically display increased aerobic glycolysis (the Warburg effect), as seen in other malignancies. However, increasing evidence suggests that advanced prostate cancer exhibits the Warburg effect and displays high glucose uptake. We describe here that trans-gnetin H (TGH), a naturally-occurring resveratrol trimer extracted from Paeonia suffruticosa, displays significant anti-cancer effects in advanced prostate cancer cells xenografted PC-3 cells in vivo.TGH perturbs energy metabolism by blocking the availability of glucose and inducing profound metabolic and transcriptomic changes in prostate cancer cells as demonstrated by RNA-seq. C-MYC, a known driver oncogene in prostate cancer, is downregulated in TGH-treated cells. Our studies demonstrate the feasibility of targeting aerobic glucose metabolism in advanced prostate cancer and identify TGH as a potential therapeutic candidate.

2023-10-01 | GSE240101 | GEO

Starving advanced prostate cancer cells by pharmacological gluose deprivation with a resveratrol trimer trans-Gnetin H [TGH]

Project description:Prostate cancer is a unique disease from a metabolic perspective. Early stage localized prostate cancer does not typically display increased aerobic glycolysis (the Warburg effect), as seen in other malignancies. However, increasing evidence suggests that advanced prostate cancer exhibits the Warburg effect and displays high glucose uptake. We describe here that trans-gnetin H (TGH), a naturally-occurring resveratrol trimer extracted from Paeonia suffruticosa, displays significant anti-cancer effects in advanced prostate cancer cells in vitro. TGH perturbs energy metabolism by blocking the availability of glucose, inducing unfolded protein response (UPR) and C-MYC pathway downregulation in PC-3 cells. Our studies demonstrate the feasibility of targeting aerobic glucose metabolism in advanced prostate cancer and identify TGH as a potential therapeutic candidate.

2023-10-01 | GSE240103 | GEO

Expression data from Drosophila melanogaster err mutant animals vs. wild type animals at a mid-second instar larval time

2011-02-02 | GSE23336 | GEO

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples

2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress

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Project description:Understanding the mechanisms of the Warburg shift to aerobic glycolysis is central to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by bi-allelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed of the mitochondrial in tumors from HLRCC patients. Biochemical and transcriptomics analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of expression of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

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2020-10-30 | E-MTAB-7619 | biostudies-arrayexpress

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