Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics

Rui Vasco Simoes; Rafael Neto Henriques; Jonas L. Olesen; Beatriz M. Cardoso; Francisca F. Fernandes; Mariana A.V. Monteiro; Sune N. Jespersen; Tânia Carvalho; Noam Shemesh

doi:10.7554/eLife.100570

Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics

Rui Vasco Simoes, Rafael Neto Henriques, Jonas L. Olesen, Beatriz M. Cardoso, Francisca F. Fernandes, Mariana A.V. Monteiro, Sune N. Jespersen, Tânia Carvalho, Noam Shemesh

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.

Original language	English
Journal	eLife
Volume	13
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.100570
Publication status	Published - Mar 2025

Keywords

cancer biology
deuterium metabolic imaging
glioblastoma
glycolysis
kinetic modeling
mitochondrial metabolism
mouse

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@article{34470451a02541b0b9bf19d2b6076ded,

title = "Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics",

abstract = "Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.",

keywords = "cancer biology, deuterium metabolic imaging, glioblastoma, glycolysis, kinetic modeling, mitochondrial metabolism, mouse",

author = "Simoes, {Rui Vasco} and Henriques, {Rafael Neto} and Olesen, {Jonas L.} and Cardoso, {Beatriz M.} and Fernandes, {Francisca F.} and Monteiro, {Mariana A.V.} and Jespersen, {Sune N.} and T{\^a}nia Carvalho and Noam Shemesh",

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year = "2025",

month = mar,

doi = "10.7554/eLife.100570",

language = "English",

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journal = "eLife",

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T1 - Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics

AU - Simoes, Rui Vasco

AU - Henriques, Rafael Neto

AU - Olesen, Jonas L.

AU - Cardoso, Beatriz M.

AU - Fernandes, Francisca F.

AU - Monteiro, Mariana A.V.

AU - Jespersen, Sune N.

AU - Carvalho, Tânia

AU - Shemesh, Noam

PY - 2025/3

Y1 - 2025/3

N2 - Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.

AB - Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.

KW - cancer biology

KW - deuterium metabolic imaging

KW - glioblastoma

KW - glycolysis

KW - kinetic modeling

KW - mitochondrial metabolism

KW - mouse

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SN - 2050-084X

VL - 13

JO - eLife

JF - eLife

ER -

Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics

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