OSCR

Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans.

Overview

Authors: Tong Tong1,2, Josephine D Hendriksen3,4, Kirstine J Elbæk1,2, Kata Molnar5,6, Freja V Christiansen5, Attila Ozsvar2,7, Jens T Eschen1,2, Francisco G Rodríguez-González3,4, Ilayda D Pusat1,2, Emilie Littau Christensen1,2, Mads Rahbæk1,2, Kathrine Pii Frederiksen1,2, Søren O S Cortnum1, Ann K Sindby1, Kaare Meier, Nikola, Jens C H Sørensen1,2, Jonathan T Ting8, Marco Capogna7, Bjarne W Kristensen9,3,10, Jens R Nyengaard5,11, Joachim Weischenfeldt3,4,10, Wen-Hsien Hou7, Anders R Korshøj1,2,10
ORCID iDs: Tong Tong, Josephine D Hendriksen, Kirstine J Elbæk, Kata Molnar, Freja V Christiansen, Attila Ozsvar, Jens T Eschen, Francisco G Rodríguez-González, Ilayda D Pusat, Emilie Littau Christensen, Mads Rahbæk, Kathrine Pii Frederiksen, Kaare Meier, Nikola, Jens C H Sørensen, Jonathan T Ting, Jens R Nyengaard, Joachim Weischenfeldt, Wen-Hsien Hou, Anders R Korshøj
  1. Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark
  2. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  3. Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
  4. Finsen Laboratoriet, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
  5. Core Center for Molecular Morphology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  6. Sino-Danish College (SDC), University of Chinese Academy of Sciences, Beijing, China
  7. Department of Biomedicine, Aarhus University, Aarhus, Denmark
  8. Allen Institute for Brain Science, Seattle, WA, USA
  9. Department of Pathology, The Bartholin Institute, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (B.W.K.)
  10. DCCC Brain Tumor Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  11. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
Institutions: Aarhus University (Denmark); Aarhus University Hospital (Denmark); University of Copenhagen (Denmark); Copenhagen University Hospital (Denmark); Rigshospitalet (Denmark); Sino-Danish Centre for Education and Research (China); University of Chinese Academy of Sciences (China); Allen Institute for Brain Science (United States)
Journal: Neuro-oncology, volume 28, issue 6, pages 1442-1457
Dates: received 24 September 2025; accepted 13 March 2026; published online 19 March 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1093/neuonc/noag059 · PMID 41857760 · PMCID PMC13232509 · OpenAlex W7139115333
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), intracellular / patch clamp (modality), human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Connectivity
Keywords: action potential, cancer neuroscience, glioblastoma, organotypic slice culture, patch-seq
MeSH: Action Potentials*, Brain Neoplasms*, Glioblastoma*, Neocortex*, Patch-Clamp Techniques*, Single-Cell Analysis*, Animals, Gene Expression Profiling, Genomics, Humans, Tumor Cells, Cultured (* major topic)
Topic: Neural dynamics and brain function (Cognitive Neuroscience, Neuroscience), according to OpenAlex
Funding: Lundbeck; Kræftfonden; the Independent Research Fund Denmark (4285-00323B); Danish Cancer Society (R304-A17698-B5570, R295-A16770); NIH HHS (R325-2019-1490); Independent Research Fund Denmark; NIH (R325-2019-1490); Lundbeck Foundation (37741); Aarhus University Research Fund (AUFF-E-2023-9-41); Krogh Invest and Danish Cancer Society (R295-A16770)
Citations: cited by 1 paper (Europe PMC); 52 references in the paper
Research resources: We thank the Bioimaging Core facility RRID:SCR_023876

Abstract

Background: Electrophysiological features of glioblastoma cells (GBCs) remain largely elusive, challenging our comprehension of glioblastoma pathophysiology. Spiking GABAergic-oligodendrocyte-progenitor (OPC) tumor cells were recently described in IDH-mutant glioma, correlating with prolonged patient survival. Here, we characterize single-cell features at the neocortical leading edge (LE) of glioblastoma patients using combined electrophysiological, morphological, and transcriptomic profiling.

Methods: We examined GBCs and non-tumor cells using acute and cultured organotypic slices of cancer-infiltrated neocortical tissues from glioblastoma patients. Electrophysiological properties of LE cells were investigated using whole-cell patch-clamp recording, with dye loading to characterize single-cell morphology. We used Patch-seq to determine the transcriptomic features of recorded LE cells and discriminate tumor and non-tumor cells, followed by gene set enrichment analysis and CellChat to identify differential gene expression and signaling.

Results: Upon depolarization, more than half of LE cells show aberrant action potentials (aAPs), akin to neurodevelopmental cells. Reconstructed LE cells have abnormal somatodendritic morphology. Patch-seq revealed that GBCs and non-tumor cells share a similar electrophysiological phenotype, including aAP generation, depolarized membrane potential, and elevated input resistance. Transcriptomic analysis shows that the aAP phenotype occurs across diverse GBC states and correlates with lower enrichment of proliferation-related pathways at the single-cell level, but higher enrichment of inflammatory/immune, angiogenic, and mesenchymal transition pathways. Non-tumor cells exhibit hybrid transcriptomic signatures, with predominantly neuronal but minor enrichment of astrocytic features.

Conclusion: We find electrophysiological aAP behavior of GBCs in human glioblastoma, closely resembling that of hybrid cells in IDH-mutant glioma, supporting the hypothesis of neuronal mimicry across different glioma types.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data Availability

The count matrix for the single-nucleus RNA sequencing dataset is uploaded to GEO (GSE315516 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315516)). The data will be made available upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 24 authors, 5 keywords, 11 MeSH terms, 9 funders, 51 references, 1 RRID.

Cite

This paper

Tong, T., Hendriksen, J. D., Elbæk, K. J., Molnar, K., Christiansen, F. V., Ozsvar, A., Eschen, J. T., Rodríguez-González, F. G., Pusat, I. D., Christensen, E. L., Rahbæk, M., Frederiksen, K. P., Cortnum, S. O. S., Sindby, A. K., Meier, K., Nikola, Sørensen, J. C. H., Ting, J. T., Capogna, M., . . . Korshøj, A. R. (2026). Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans. Neuro-oncology, 28(6), 1442-1457. https://doi.org/10.1093/neuonc/noag059

BibTeX

@article{tong2026combined,
author = {Tong, Tong and Hendriksen, Josephine D and Elbæk, Kirstine J and Molnar, Kata and Christiansen, Freja V and Ozsvar, Attila and Eschen, Jens T and Rodríguez-González, Francisco G and Pusat, Ilayda D and Christensen, Emilie Littau and Rahbæk, Mads and Frederiksen, Kathrine Pii and Cortnum, Søren O S and Sindby, Ann K and Meier, Kaare and Nikola and Sørensen, Jens C H and Ting, Jonathan T and Capogna, Marco and Kristensen, Bjarne W and Nyengaard, Jens R and Weischenfeldt, Joachim and Hou, Wen-Hsien and Korshøj, Anders R},
title = {{Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans}},
journal = {Neuro-oncology},
year = {2026},
month = jun,
volume = {28},
number = {6},
pages = {1442--1457},
publisher = {Oxford University Press},
issn = {1522-8517},
doi = {10.1093/neuonc/noag059},
url = {https://doi.org/10.1093/neuonc/noag059},
pmid = {41857760},
pmcid = {PMC13232509}
}

RIS

TY - JOUR
AU - Tong, Tong
AU - Hendriksen, Josephine D
AU - Elbæk, Kirstine J
AU - Molnar, Kata
AU - Christiansen, Freja V
AU - Ozsvar, Attila
AU - Eschen, Jens T
AU - Rodríguez-González, Francisco G
AU - Pusat, Ilayda D
AU - Christensen, Emilie Littau
AU - Rahbæk, Mads
AU - Frederiksen, Kathrine Pii
AU - Cortnum, Søren O S
AU - Sindby, Ann K
AU - Meier, Kaare
AU - Nikola
AU - Sørensen, Jens C H
AU - Ting, Jonathan T
AU - Capogna, Marco
AU - Kristensen, Bjarne W
AU - Nyengaard, Jens R
AU - Weischenfeldt, Joachim
AU - Hou, Wen-Hsien
AU - Korshøj, Anders R
TI - Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans
T2 - Neuro-oncology
J2 - Neuro Oncol
PY - 2026
DA - 2026/06/01
VL - 28
IS - 6
SP - 1442
EP - 1457
SN - 1522-8517
PB - Oxford University Press
DO - 10.1093/neuonc/noag059
UR - https://doi.org/10.1093/neuonc/noag059
LA - en
ER -

CSL-JSON

{
"id": "10.1093/neuonc/noag059",
"type": "article-journal",
"title": "Combined patch-clamp electrophysiology and single-cell genomic analysis reveal spiking tumor cells at the neocortical glioblastoma interface in humans",
"container-title": "Neuro-oncology",
"author": [
{
"family": "Tong",
"given": "Tong"
},
{
"family": "Hendriksen",
"given": "Josephine D"
},
{
"family": "Elbæk",
"given": "Kirstine J"
},
{
"family": "Molnar",
"given": "Kata"
},
{
"family": "Christiansen",
"given": "Freja V"
},
{
"family": "Ozsvar",
"given": "Attila"
},
{
"family": "Eschen",
"given": "Jens T"
},
{
"family": "Rodríguez-González",
"given": "Francisco G"
},
{
"family": "Pusat",
"given": "Ilayda D"
},
{
"family": "Christensen",
"given": "Emilie Littau"
},
{
"family": "Rahbæk",
"given": "Mads"
},
{
"family": "Frederiksen",
"given": "Kathrine Pii"
},
{
"family": "Cortnum",
"given": "Søren O S"
},
{
"family": "Sindby",
"given": "Ann K"
},
{
"family": "Meier",
"given": "Kaare"
},
{
"family": "Nikola"
},
{
"family": "Sørensen",
"given": "Jens C H"
},
{
"family": "Ting",
"given": "Jonathan T"
},
{
"family": "Capogna",
"given": "Marco"
},
{
"family": "Kristensen",
"given": "Bjarne W"
},
{
"family": "Nyengaard",
"given": "Jens R"
},
{
"family": "Weischenfeldt",
"given": "Joachim"
},
{
"family": "Hou",
"given": "Wen-Hsien"
},
{
"family": "Korshøj",
"given": "Anders R"
}
],
"container-title-short": "Neuro Oncol",
"volume": "28",
"issue": "6",
"page": "1442-1457",
"DOI": "10.1093/neuonc/noag059",
"PMID": "41857760",
"PMCID": "PMC13232509",
"ISSN": "1522-8517",
"publisher": "Oxford University Press",
"URL": "https://doi.org/10.1093/neuonc/noag059",
"language": "en",
"issued": {
"date-parts": [
[
2026,
6,
1
]
]
}
}

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1038/s41467-026-76587-0 [code]
Uncovering the signaling networks of disseminated glioblastoma cells in vivo with INSIGHT.
Journal: Nature communications
In common: genetics / omics, other condition, cellular / molecular, 8 references
[2] doi:10.1038/s41586-026-10631-3 [code]
A prognostic human brain network for diffuse midline glioma.
Journal: Nature
In common: other condition, 8 references
[3] doi:10.3389/fncel.2026.1713437 [code]
Single-nucleus transcriptomics identifies cell cycle and synaptic pathway dysregulation during OPC-to-glioma progression.
Journal: Frontiers in cellular neuroscience
In common: genetics / omics, other condition, cellular / molecular, 8 references
[4] doi:10.1016/j.xcrm.2026.102766 [code]
A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.
Journal: Cell reports. Medicine
In common: genetics / omics, other condition, cellular / molecular, 8 references
[5] doi:10.3390/ijms27104300
A Synaptogenesis-Associated Histomorphologic Signature from H&E Whole-Slide Images Predicts Glioma Prognosis and Identifies <i>EFNB2</i>-Positive Malignant Cells as a Candidate Neuro-Glioma Communication Hub.
Journal: International journal of molecular sciences
In common: genetics / omics, other condition, 7 references
[6] doi:10.1186/s40478-026-02312-z
Dissecting acute neuronal responses to glioblastoma using a dual-interface human iPSC neuronal culture platform.
Journal: Acta neuropathologica communications
In common: other condition, cellular / molecular, 6 references
[7] doi:10.1186/s12967-026-08266-z [code]
Single-cell multi-omic integration analysis prioritizes druggable genes and reveals cell-type-specific causal effects in glioblastomagenesis.
Journal: Journal of translational medicine
In common: genetics / omics, other condition, cellular / molecular, 5 references
[8] doi:10.1016/j.isci.2026.115361
Glioblastoma invasion into different organoid hosts reveals cell-intrinsic and proliferative migratory programs.
Journal: iScience
In common: other condition, cellular / molecular, 5 references
[9] doi:10.3390/ijms27136068 [code]
Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis.
Journal: International journal of molecular sciences
In common: genetics / omics, other condition, cellular / molecular, 5 references
[10] doi:10.1038/s41586-026-10214-2 [code]
Multidimensional profiling of heterogeneity in supratentorial ependymomas.
Journal: Nature
In common: genetics / omics, other condition, 4 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.