Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Abstract: Background
A major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials.
Methods
Here, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry, and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors.
Results
We show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood–brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components.
Conclusions
Our data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Genome medicine. - 16, 1 (2024) , 51, ISSN: 1756-994X
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
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Universität
- (when)
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2024
- Creator
- DOI
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10.1186/s13073-024-01321-8
- URN
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urn:nbn:de:bsz:25-freidok-2490939
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:53 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Yabo, Yahaya A.
- Heiland, Dieter Henrik
- Michelucci, Alessandro
- Golebiewska, Anna
- Universität
Time of origin
- 2024
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Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor
Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts
Dasatinib enhances tumor growth in gemcitabine-resistant orthotopic bladder cancer xenografts
Patient-derived xenografts as preclinical neuroblastoma models
Magnetic resonance imaging-guided intracranial resection of glioblastoma tumors in patient-derived orthotopic xenografts leads to clinically relevant tumor recurrence
Molecular profiling of patient-derived breast cancer xenografts
Patient-derived tumor immune microenvironments in patient-derived xenografts of lung cancer
Patient-derived xenografts as compatible models for precision oncology
Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach
Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts
Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor
Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts
Dasatinib enhances tumor growth in gemcitabine-resistant orthotopic bladder cancer xenografts
Patient-derived xenografts as preclinical neuroblastoma models
Magnetic resonance imaging-guided intracranial resection of glioblastoma tumors in patient-derived orthotopic xenografts leads to clinically relevant tumor recurrence
Molecular profiling of patient-derived breast cancer xenografts
Patient-derived tumor immune microenvironments in patient-derived xenografts of lung cancer
Patient-derived xenografts as compatible models for precision oncology