Tissue-reactive zonation of mesenchymal-like phenotypes in human glioblastoma
8 affiliations
- 1Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
- 2Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, 17164 Stockholm, Sweden
- 3Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden; Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, 17164 Stockholm, Sweden
- 4Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden; Center for Brain & Disease Research, VIB, 3000 Leuven, Belgium; Center for AI & Computational Biology, VIB, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium
- 5Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, 17164 Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institute, 17177 Stockholm, Sweden
- 6Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden; Department of Translational Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands
- 7Department of Clinical Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden; Department of Neurosurgery, Karolinska University Hospital, 17164 Stockholm, Sweden
- 8Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden. Electronic address: [email protected]
Abstract
BACKGROUND: Glioblastoma is the deadliest brain cancer, characterized by large cellular diversity. Both neurodevelopment-like and mesenchymal-like cell states have been described, with the latter being strongly implicated in malignancy and disease progression. However, the spatial organization of these mesenchymal-like cell states has not been systematically described outside the tumor bulk. METHODS: We performed deep single-cell RNA sequencing of rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex and 888-plex enhanced electric single-molecule fluorescence in situ hybridization (EEL-FISH) spatial transcriptomics on a large cohort of standard resections. We also established four glioblastoma organoid lines to test in vitro inducibility of mesenchymal-like cell states under hypoxia and blood plasma exposure. FINDINGS: We discovered that previously defined mesenchymal-like tumor cell states were shared across both malignant and non-malignant cell types and spatially confined to the tumor bulk. Peripheral regions were instead dominated by neurodevelopment-like tumor states and endogenous microglia. In patient-derived organoids and non-malignant astrocytes, the mesenchymal transcriptional state could be reversibly induced in vitro by hypoxia and human plasma, indicative of a wound response. Multiplex single-molecule spatial transcriptomics revealed that the activation of mesenchymal-like states was associated with hypoxia and organized by distance to perivascular niches. CONCLUSIONS: Our findings clarify the cellular landscape and biology of glioblastoma, wherein the mesenchymal state arises at least partly as a reactive tissue state shared by all cells in the tumor bulk. FUNDING: This work was supported by Region Stockholm, Erling-Persson Family Foundation (Atlas of Childhood Disease), Hjärnfonden (FO2023-0309), Swedish Research Council (2022-01248), and Torsten Söderberg Foundation.
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BibTeX
@article{albiach2026tissuereactive,
title = {{Tissue-reactive zonation of mesenchymal-like phenotypes in human glioblastoma}},
author = {Alejandro Mossi Albiach and Jokubas Janusauskas and Jesper Kjaer Jacobsen and Ivana Kapustová and Razieh Karamzadeh and Egle Kvedaraite and Lijuan Hu and Marina C. M. Franck and Maria Ramal García and David Fernández-García and Camiel C. A. Mannens and Simone Codeluppi and Johannes B. Munting and Lars E. Borm and Alia Shamikh and Peter Lönnerberg and Kimberly Siletti and Oscar Persson and Sten Linnarsson},
journal = {Med},
year = {2026},
month = jul,
doi = {10.1016/j.medj.2026.101228},
url = {https://doi.org/10.1016/j.medj.2026.101228},
note = {CC BY},
}
RIS
TY - JOUR
TI - Tissue-reactive zonation of mesenchymal-like phenotypes in human glioblastoma
AU - Alejandro Mossi Albiach
AU - Jokubas Janusauskas
AU - Jesper Kjaer Jacobsen
AU - Ivana Kapustová
AU - Razieh Karamzadeh
AU - Egle Kvedaraite
AU - Lijuan Hu
AU - Marina C. M. Franck
AU - Maria Ramal García
AU - David Fernández-García
AU - Camiel C. A. Mannens
AU - Simone Codeluppi
AU - Johannes B. Munting
AU - Lars E. Borm
AU - Alia Shamikh
AU - Peter Lönnerberg
AU - Kimberly Siletti
AU - Oscar Persson
AU - Sten Linnarsson
PY - 2026
DA - 2026/07/23
JO - Med
DO - 10.1016/j.medj.2026.101228
UR - https://doi.org/10.1016/j.medj.2026.101228
AB - BACKGROUND: Glioblastoma is the deadliest brain cancer, characterized by large cellular diversity. Both neurodevelopment-like and mesenchymal-like cell states have been described, with the latter being strongly implicated in malignancy and disease progression. However, the spatial organization of these mesenchymal-like cell states has not been systematically described outside the tumor bulk. METHODS: We performed deep single-cell RNA sequencing of rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex and 888-plex enhanced electric single-molecule fluorescence in situ hybridization (EEL-FISH) spatial transcriptomics on a large cohort of standard resections. We also established four glioblastoma organoid lines to test in vitro inducibility of mesenchymal-like cell states under hypoxia and blood plasma exposure. FINDINGS: We discovered that previously defined mesenchymal-like tumor cell states were shared across both malignant and non-malignant cell types and spatially confined to the tumor bulk. Peripheral regions were instead dominated by neurodevelopment-like tumor states and endogenous microglia. In patient-derived organoids and non-malignant astrocytes, the mesenchymal transcriptional state could be reversibly induced in vitro by hypoxia and human plasma, indicative of a wound response. Multiplex single-molecule spatial transcriptomics revealed that the activation of mesenchymal-like states was associated with hypoxia and organized by distance to perivascular niches. CONCLUSIONS: Our findings clarify the cellular landscape and biology of glioblastoma, wherein the mesenchymal state arises at least partly as a reactive tissue state shared by all cells in the tumor bulk. FUNDING: This work was supported by Region Stockholm, Erling-Persson Family Foundation (Atlas of Childhood Disease), Hjärnfonden (FO2023-0309), Swedish Research Council (2022-01248), and Torsten Söderberg Foundation.
SN - 2666-6340
SN - 2666-6359
ER -