Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis

Guillermier, Christelle; Doherty, Sean; Whitney, Adam; Babaev, Vladimir R.; Linton, MacRae F.; Steinhauser, Matthew L.; Brown, J.

doi:10.1172/jci.insight.128528

Cited by 23 publications

(37 citation statements)

References 23 publications

(45 reference statements)

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“…In order to assess the degree of tumor metabolic heterogeneity in vivo , we utilized MIMS to track labeled metabolic substrates, using a cocktail consisting of 2 H-glucose, 15 N-glutamine, and BrdU administered over 24 h to murine tumor models ( Figure 2 A). Our choice of label dose reflected our goal to achieve sufficiently high labeling in order to facilitate label detection within a reasonable amount of time and prior experience with amino acid and glucose metabolic labeling in other physiological or pathophysiological contexts ( Guillermier et al., 2017b , 2019 ; Zhang et al., 2012 ). We first labeled an Nf1 +/− ;Tp53 +/− mouse model of malignant peripheral nerve sheath tumor (MPNST), incidentally finding a second intra-abdominal histiosarcoma, which in both tumor types is caused by a stochastic loss of wild-type Nf1 and Tp53 alleles.…”

Section: Resultsmentioning

confidence: 99%

“…Prior applications of MIMS to non-cancerous tissues has provided a framework to quantify stable isotope-tagged glucose, amino acids, and precursors of nucleic acid synthesis in a multiplexed fashion ( Guillermier et al., 2017b , 2019 ; Steinhauser et al., 2012 ; Zhang et al., 2012 ). We reasoned that MIMS could also enable quantitative measurement of substrate utilization in individual cancer cells, thereby enabling us to test the hypothesis that tumors exhibit metabolic heterogeneity at the level of individual cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Imaging Mass Spectrometry Reveals Tumor Metabolic Heterogeneity

et al. 2020

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Summary Malignant tumors exhibit high degrees of genomic heterogeneity at the cellular level, leading to the view that subpopulations of tumor cells drive growth and treatment resistance. To examine the degree to which tumors also exhibit metabolic heterogeneity at the level of individual cells, we employed multi-isotope imaging mass spectrometry (MIMS) to quantify utilization of stable isotopes of glucose and glutamine along with a label for cell division. Mouse models of melanoma and malignant peripheral nerve sheath tumors (MPNSTs) exhibited striking heterogeneity of substrate utilization, evident in both proliferating and non-proliferating cells. We identified a correlation between metabolic heterogeneity, proliferation, and therapeutic resistance. Heterogeneity in metabolic substrate usage as revealed by incorporation of glucose and glutamine tracers is thus a marker for tumor proliferation. Collectively, our data demonstrate that MIMS provides a powerful tool with which to dissect metabolic functions of individual cells within the native tumor environment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Imaging Mass Spectrometry Reveals Tumor Metabolic Heterogeneity

et al. 2020

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“…However, the underlying molecular and metabolic mechanisms remain unknown. A recent study using multi-isotope imaging mass spectrometry found that plaque proliferating cells used preferentially glucose in comparison to neighboring non-proliferating cells [21]. Surprisingly, foamy cells were highly glucose consuming and this was correlated with increased proliferation [21].…”

Section: Immune Cell Diversity In Atherosclerotic Plaquementioning

confidence: 99%

Macrophage metabolic regulation in atherosclerotic plaque

et al. 2021

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Metabolism plays a key role in controlling immune cell functions. In this review, we will discuss the diversity of plaque resident myeloid cells and will focus on their metabolic demands that could reflect on their particular intraplaque localization. Defining the metabolic configuration of plaque resident myeloid cells according to their topologic distribution could provide answers to key questions regarding their functions and contribution to disease development.

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“…Nevertheless, recent studies have demonstrated the feasibility of different techniques for profiling the metabolome at the single-cell level from both cell cultures [67,68] and freshly resected tissues [69]. Among these techniques, mass spectrometry imaging (MSI) spatial metabolomics [70] is perhaps the most widely applicable, with the proven ability to characterize both metabolite levels and isotopic-labeling patterns at subcellular (and even suborganelle) resolutions [71]. The current caveat of MSI-based approaches is a necessary tradeoff between spatial resolution, metabolite coverage, and sensitivity.…”

Section: Box 3 Interpreting In Vivo Tracer Measurements (1): Pathwaymentioning

confidence: 99%

Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo

Fernández-García

Altea-Manzano

Pranzini

et al. 2020

Trends in Biochemical Sciences

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Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field. Metabolism: A Central Node for Cellular Processes Metabolism can be seen as the engine of the cell, providing energy, redox cofactors, and building blocks for cell maintenance, growth, and renewal, as well as playing a key role in modulating cell signaling [1,2]. To orchestrate all these functions, metabolism consists of a complex network of genes, enzymes, and metabolites, steadily modulated in response to different stimuli [3-5]. Defining the mechanisms at the basis of this regulation and understanding their physiological role is among the most important pursuits in biological and medical research [6], particularly since the realization that many pathologies are driven by metabolic deregulations [7]. An in-depth understanding of metabolic pathways in vivo and how these are deregulated in different diseases is thus fundamental for the discovery of new therapeutic targets and clinical biomarkers, enabling the development of more robust diagnosis approaches and personalized treatments, eventually improving the overall outcome for patients [8]. In this context, stable-isotope tracers (see Glossary) have become a standard for probing cellular metabolism [9] and their increasing implementation in in vivo settings has revolutionized our current understanding of mammalian metabolism in health and disease, unraveling novel regulatory principles at both the cellular and whole-organism level [10,11]. In this review, we summarize the latest advances in in vivo metabolic measurements using stable-isotope tracers, highlighting the importance of systems-level integrative approaches and careful experimental design, pointing out open challenges and opportunities for advancing the field, and outlining strategies and potential pitfalls when interpreting these measurements (Figure 1). Tracer-Based Methods for Measuring Cellular Metabolism In Vivo Many complementary methods exist to study metabolism in vivo and, consequently, the selection of a specific approach (or set of approaches) depends largely on the biological question being addressed. Nontracer-based methods, such as assessing bioenergetics by measuring dynamic changes in oxygen consumption [12] or evaluating changes in metabolite levels via metabolomics [13],...

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Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis

Cited by 23 publications

References 23 publications

Imaging Mass Spectrometry Reveals Tumor Metabolic Heterogeneity

Imaging Mass Spectrometry Reveals Tumor Metabolic Heterogeneity

Macrophage metabolic regulation in atherosclerotic plaque

Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo

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