Evidence map›Paper›PMID 41137658›Full record

ArticleNeuro-oncology2026

Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.

Milan R Savani, Mohamad El Shami, Kenji Miki, Lauren C Gattie, Bailey C Smith, William H Hicks, Jacob O Weiss, Skyler S Oken, Lavanya N Katta, Tracey Shipman and 14 more

Abstract read
In one paragraph

Article in Neuro-oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
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  3. Review
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  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors.

Milan R SavaniChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0003-1776-451X
Mohamad El ShamiDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0000-0001-7345-4247
Kenji MikiDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0000-0001-7424-0021
Lauren C GattieDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0009-0002-9437-0610
Bailey C SmithChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0009-0001-4719-4581
William H HicksChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-2689-3199
Jacob O WeissChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0009-0004-5965-2326
Skyler S OkenDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0009-0002-4503-7395
Lavanya N KattaChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0009-0006-3956-9976
Tracey ShipmanChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0009-0004-4497-7080
Maged T GhocheDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0009-0001-6679-681X
Lauren G ZachariasChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0009-0007-7413-6460
Misty S Martin-SandovalChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-7646-4181
Eric Y MontgomeryChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0001-8255-2455
Yi XiaoChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-3817-3471
Diana D ShiChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-6626-5277
Jeremy N RichLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill (J.N.R.).ORCID 0000-0001-7845-5302
Timothy E RichardsonDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York (T.E.R.).ORCID 0000-0001-7068-5517
Pascal O ZinnDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0000-0003-0091-5887
Bradley C LegaDepartment of Neurosurgery, UT Southwestern Medical Center, Dallas (B.C.L.).ORCID 0000-0003-3634-406X
Thomas P MathewsChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-9355-8243
Ralph J DeBerardinisChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0002-2705-7432
Kalil G AbdullahDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (M.E.S., K.M., L.C.G., W.H.H., S.S.O., M.T.G., P.O.Z., K.G.A.).ORCID 0000-0002-5662-0829
Samuel K McBrayerChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas (M.R.S., B.C.S., W.H.H., J.O.W., L.N.K., T.S., L.G.Z., M.S.M.-S., E.Y.M., Y.X., D.D.S., T.P.M., R.J.D., S.K.M.).ORCID 0000-0001-9361-675X

Funding

Targeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Tracy T Batchelor · 2013 to 2026
$33.5M
UT Southwestern NORCP30DK127984 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI JAY D. HORTON · 2022 to 2026
$7.4M
Targeting the neuronal microenvironment in glioblastomaU19CA264504 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI Michelle Monje-Deisseroth · 2021 to 2026
$6.4M
Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma TherapyR01CA258586 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI ABDULLAH, KALIL G, MCBRAYER, SAMUEL KENT · 2021 to 2025
$1.8M
Development of a nuclear alpha-ketoglutarate biosensor system to study metabolic control of the epigenomeR01GM158820 · NIGMS · UT SOUTHWESTERN MEDICAL CENTER · PI MCBRAYER, SAMUEL KENT · 2025 to 2025
$1.8M
Metabolic mechanisms of glioma progressionR01CA289260 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI Kalil G Abdullah, Samuel Kent McBrayer · 2025 to 2026
$1.3M
Mechanisms of glioma initiation by IDH oncogenesR01NS142141 · NINDS · UT SOUTHWESTERN MEDICAL CENTER · PI Samuel Kent McBrayer · 2025 to 2026
$1.3M
Defining mechanisms of metabolic-epigenetic crosstalk that drive glioma initiationK99CA277576 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI XIAO, YI · 2023 to 2024
$248k
Dissecting Mechanisms of Pyrimidine Synthesis Dependence in IDH Mutant GliomaF30CA271634 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI SAVANI, MILAN RASHMIN · 2022 to 2025
$171k
Cancer Prevention and Research Institute of Texas RP230344Cancer Prevention and Research Institute of Texas RP240489Cancer Prevention and Research Institute of Texas RR190034Cancer Prevention Research Institute of TexasChildren's Research Institute MetabolomicsCore Facilities RP240494Human Frontier Science Program postdoctoral LT0018/2022-LNCI NIH HHS F30 CA271634NCI NIH HHS K99 CA277576NCI NIH HHS K99CA277576NCI NIH HHS P50 CA165962NCI NIH HHS R01 CA258586NCI NIH HHS R01 CA289260NCI NIH HHS U19 CA264504NIDDK NIH HHS P30 DK127984NIGMS NIH HHS R01 GM158820NIHNIH HHS F30CA271634NIH HHS P50CA165962NIH HHS R01CA258586NIH HHS R01CA289260NIH HHS R01GM158820NIH HHS R01NS142141NIH HHS U19CA264504NINDS NIH HHS R01 NS142141Oligo Nation
6 · The paper itself

Abstract

backgroundIn vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.

methodsWe optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.

resultsHuman plasma-like medium culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic guanosine diphosphate mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.

conclusionsWe present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.

Indexed as

Brain NeoplasmsCulture MediaGlioblastomaIsotope LabelingTumor MicroenvironmentHumansNeoplastic Stem CellsNitrogen IsotopesTumor Cells, CulturedCulture MediaNitrogen Isotopesgliomametabolismorganoidspreclinical modelsstable isotope tracing

Identifiers

PMID41137658
PMCPMC12979037

What Socratic holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.