Liquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics

Li, Ziming; Wang, Zhuo; Tang, Yin; Lü, Xiang; Chen, Jie; Dong, Yu; Wu, Baojun; Wang, Qianqian; Liu, Yang; Guo, Zhiyong; Xue, Min; Lü, Shun; Wei, Wei; Shi, Qi

doi:10.1038/s41467-019-11808-3

Cited by 40 publications

(31 citation statements)

References 76 publications

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“…In addition, several groups have shown that 2-NBDG is useful for monitoring aberrant cellular uptake of d-glucose in tumors in vitro and in vivo [137][138][139][140][141][142][143][144][145]. 2-NBDG has been effectively applied to clinical specimens as well such as biopsy tissues obtained from patients with oral cancer [146,147], esophagus cancer [148], head and neck cancer [149], breast cancer [150], colorectal cancer [151], and for metabolic phenotyping or screening of cancerous cells in pleural effusion or peripheral blood obtained from lung cancer patients [152,153].…”

Section: Uptake Of 2-nbdg Into Mammalian Cells Through Gluts and Its mentioning

confidence: 99%

“…Indeed, successful evaluations of clinical specimens by 2-NBDG have been reported [146][147][148][149][150]. Another possibility is to use 2-NBDG as a marker for metabolic phenotyping of body fluid [152,153,167]. GB2-Cy3 (Em, 555 nm) was synthesized by attaching Cy3, a cyanine dye much smaller than Cy5.5, to C-1 position of d-glucose via a long linker [159] (Figure 4).…”

Section: Development Of D-glucose Analogues That Emit Fluorescence Ofmentioning

confidence: 99%

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L-Glucose: Another Path to Cancer Cells

Ono

Takigawa

Yamada

2020

Cancers

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Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l-glucose, the mirror image isomer of naturally occurring d-glucose; l-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with l-glucose, we generated fluorescence-emitting l-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent d-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells.

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Section: Uptake Of 2-nbdg Into Mammalian Cells Through Gluts and Its mentioning

confidence: 99%

Section: Development Of D-glucose Analogues That Emit Fluorescence Ofmentioning

confidence: 99%

L-Glucose: Another Path to Cancer Cells

Ono

Takigawa

Yamada

2020

Cancers

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“…Mass spectrometric analysis of single circulating cancer cells from the blood of patients revealed metabolites that differed among various kinds of cancer cells ( Hiyama et al, 2015 ; Abouleila et al, 2019 ). Fluorescent probes have also been used to characterize metabolism in circulating cancer cells ( Li et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

DeVilbiss

Zhao

Martin-Sandoval

et al. 2021

eLife

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Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically isolated hematopoietic stem cells (HSCs) that detects 60 metabolites in 10,000 cells (Agathocleous et al., 2017). Here we describe a new method involving hydrophilic liquid interaction chromatography and high-sensitivity orbitrap mass spectrometry that detected 160 metabolites in 10,000 HSCs, including many more glycolytic and lipid intermediates. We improved chromatographic separation, increased mass resolution, minimized ion suppression, and eliminated sample drying. Most metabolite levels did not significantly change during cell isolation. Mouse HSCs exhibited increased glycerophospholipids relative to bone marrow cells and methotrexate treatment altered purine biosynthesis. Circulating human melanoma cells were depleted for purine intermediates relative to subcutaneous tumors, suggesting decreased purine synthesis during metastasis. These methods facilitate the routine metabolomic analysis of rare cells from tissues.

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“…Mass spectrometric analysis of single circulating cancer cells from the blood of patients revealed metabolites that differed among various kinds of cancer cells (Hiyama et al, 2015. Fluorescent probes have also been used to characterize metabolism in circulating cancer cells (Li et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

DeVilbiss

Zhao

Martin-Sandoval

et al. 2020

Preprint

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Little is known about the metabolic regulation of rare cell populations because most metabolites are hard to detect in small numbers of cells. We previously described a method for metabolomic profiling of flow cytometrically-isolated hematopoietic stem cells (HSCs) that detects approximately 60 metabolites in 10,000 cells (Agathocleous et al., 2017). Here we describe a new method involving hydrophilic liquid interaction chromatography (HILIC) and high-sensitivity orbitrap mass spectrometry that detected approximately 160 metabolites in 10,000 HSCs, including many more glycolytic and lipid intermediates. We improved chromatographic separation, increased mass resolution, minimized ion suppression, extracted with acetonitrile, and eliminated sample drying. Most metabolites did not significantly change during cell preparation and sorting. We used this method to profile HSCs and circulating melanoma cells. HSCs exhibited increased glycerophospholipid metabolites relative to unfractionated bone marrow cells and altered purine biosynthesis after methotrexate treatment in vivo. Circulating melanoma cells were depleted for purine intermediates relative to subcutaneous tumors, suggesting they decrease purine synthesis during metastasis. These methods facilitate the routine metabolomic analysis of rare cell populations from tissues.Impact statementWe developed a method for metabolomic analysis of small numbers of flow cytometrically isolated cells from rare cell populations such as hematopoietic stem cells and circulating cancer cells.

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Liquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics

Cited by 40 publications

References 76 publications

L-Glucose: Another Path to Cancer Cells

L-Glucose: Another Path to Cancer Cells

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

Metabolomic profiling of rare cell populations isolated by flow cytometry from tissues

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