One-carbon metabolism involving the folate and methionine cycles integrates nutritional status from amino acids, glucose and vitamins, and generates diverse outputs, such as the biosynthesis of ...lipids, nucleotides and proteins, the maintenance of redox status and the substrates for methylation reactions. Long considered a 'housekeeping' process, this pathway has recently been shown to have additional complexity. Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status. Given the wealth of clinically available agents that target one-carbon metabolism, these new findings could present opportunities for translation into precision cancer medicine.
The tumor milieu consists of numerous cell types each existing in a different environment. However, a characterization of metabolic heterogeneity at single-cell resolution is not established. Here, ...we develop a computational pipeline to study metabolic programs in single cells. In two representative human cancers, melanoma and head and neck, we apply this algorithm to define the intratumor metabolic landscape. We report an overall discordance between analyses of single cells and those of bulk tumors with higher metabolic activity in malignant cells than previously appreciated. Variation in mitochondrial programs is found to be the major contributor to metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of the tumor microenvironment.
Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs - which include both nutrient availability as a result of diet and growth factor signalling - are ...implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions.
Metabolomics: A Primer Liu, Xiaojing; Locasale, Jason W.
Trends in biochemical sciences (Amsterdam. Regular ed.),
04/2017, Volume:
42, Issue:
4
Journal Article
Peer reviewed
Open access
Metabolomics generates a profile of small molecules that are derived from cellular metabolism and can directly reflect the outcome of complex networks of biochemical reactions, thus providing ...insights into multiple aspects of cellular physiology. Technological advances have enabled rapid and increasingly expansive data acquisition with samples as small as single cells; however, substantial challenges in the field remain. In this primer we provide an overview of metabolomics, especially mass spectrometry (MS)-based metabolomics, which uses liquid chromatography (LC) for separation, and discuss its utilities and limitations. We identify and discuss several areas at the frontier of metabolomics. Our goal is to give the reader a sense of what might be accomplished when conducting a metabolomics experiment, now and in the near future.
Extraction from a biological sample followed by chromatographic separation and mass spectrometry allows the simultaneous measurement of hundreds of metabolites.
The application of metabolomics to address numerous biological questions has been successfully demonstrated.
Advances in instrumentation and computational tools enable metabolomics.
Emerging technologies are further advancing metabolomics.
Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus ...coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.
One‐carbon metabolism is a metabolic network that integrates nutrient status from the environment to yield multiple biological functions. The folate and methionine cycles generate ...S‐adenosylmethionine (SAM), which is the universal methyl donor for methylation reactions, including histone and DNA methylation. Histone methylation is a crucial part of the epigenetic code and plays diverse roles in the establishment of chromatin states that mediate the regulation of gene expression. The activities of histone methyltransferases (HMTs) are dependent on intracellular levels of SAM, which fluctuate based on cellular nutrient availability, providing a link between cell metabolism and histone methylation. Here we discuss the biochemical properties of HMTs, their role in gene regulation, and the connection to cellular metabolism. Our emphasis is on understanding the specificity of this intriguing link.
The study of normal mammalian cell growth and the defects that contribute to disease pathogenesis links metabolism to cell growth. Here, we visit several aspects of growth-promoting metabolism, ...emphasizing recent advances in our understanding of how alterations in glucose metabolism affect cytosolic and mitochondrial redox potential and ATP generation. These alterations drive cell proliferation not only through supporting biosynthesis, energy metabolism, and maintaining redox potential but also through initiating signaling mechanisms that are still poorly characterized. The evolutionary basis of these additional layers of growth control is also discussed.
Acetate and the related metabolism of acetyl-coenzyme A (acetyl-CoA) confer numerous metabolic functions, including energy production, lipid synthesis, and protein acetylation. Despite its importance ...as a nutrient for cellular metabolism, its source has been unclear. Recent studies have provided evidence to support the existence of a de novo pathway for acetate production derived from pyruvate, the end product of glycolysis. This mechanism of pyruvate-derived acetate generation could have far-reaching implications for the regulation of central carbon metabolism. In this Opinion, we discuss our current understanding of acetate metabolism in the context of cell-autonomous metabolic regulation, cell–cell interactions, and systemic physiology. Applications relevant to health and disease, particularly cancer, are emphasized.
Our understanding of the origin of acetate in physiological and disease states is currently evolving and is not limited to exogenous acetate uptake.The regulation of the production of endogenous pyruvate-derived acetate remains largely unknown.Pathways of metabolism during periods of nutritional excess and limitation allow metabolic coupling to confer fitness advantages to proximal and systemic cellular partners.Preferential uptake of acetate by certain tissues is driven not only by the availability of transporters but by environmental pressures such as hypoxia and nutrient scarcity.
Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and ...fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the ‘Warburg Effect’. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.
Both glycolytic and mitochondrial metabolism are essential for cell proliferation in both past and present conceptions of the Warburg Effect.
Numerous proposals for the function of the Warburg Effect have emerged over the years.
Each of the proposed functions of the Warburg Effect is attractive, but also raises questions.
Signal transduction functions for the Warburg Effect appear likely, but are difficult to test experimentally.
Repurposing metformin for cancer therapy is attractive due to its safety profile, epidemiological evidence, and encouraging data from human clinical trials. Although it is known to systemically ...affect glucose metabolism in liver, muscle, gut, and other tissues, the molecular determinants that predict a patient response in cancer remain unknown. Here, we carry out an integrative metabolomics analysis of metformin action in ovarian cancer. Metformin accumulated in patient biopsies, and pathways involving nucleotide metabolism, redox, and energy status, all related to mitochondrial metabolism, were affected in treated tumors. Strikingly, a metabolic signature obtained from a patient with an exceptional clinical outcome mirrored that of a responsive animal tumor. Mechanistically, we demonstrate with stable isotope tracing that these metabolic signatures are due to an inability to adapt nutrient utilization in the mitochondria. This analysis provides new insights into mitochondrial metabolism and may lead to more precise indications of metformin in cancer.
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•Metformin accumulates in human tumor biopsies at micromolar concentrations•The response to metformin in humans can be modeled in nutrient-limited environments•Mitochondrial substrate utilization underlies metformin sensitivity•Restoration of specific mitochondrial outputs causes resistance to metformin
Liu et al. carry out an integrative metabolomics analysis of metformin action in ovarian cancer. Using patient samples (including those from a “super-responder”), animal tumors, and cell culture models, they find that the predominant mechanism of action by metformin in cancer is to target tumor-cell-intrinsic mitochondrial metabolism.
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