Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity Article Swipe
Zachery Moore
,
Claire Storey
,
Daniel V. Brown
,
Adam Valkovic
,
Montana Spiteri
,
Jasmine F. Pignatelli
,
Shannon J. Oliver
,
A. Fakhri
,
Katharine J. Drummond
,
Seth Malinowski
,
Keith L. Ligon
,
Oliver M. Sieber
,
James R. Whittle
,
Saskia Freytag
,
Sarah A. Best
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.01.08.632025
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.01.08.632025
The intra- and inter-tumoral heterogeneity of glioblastoma represents a significant therapeutic challenge, as well as difficulty in generating reliable models for in vitro studies. Historical 2D adherent cell lines do not recapitulate this complexity, whereas both patient-derived neurospheres (PDN) and organoids (PDO) demonstrate intra-tumoral heterogeneity. Here, we quantify the tumor cell composition from matched models established from the same primary tumor using a series of multi-omic interrogations. We find that both patient-derived models recapitulate the genomic, epigenomic and tumor cell heterogeneity of the primary tissue. Furthermore, single-nuclei RNA sequencing revealed a subset of organoids containing small numbers of non-malignant cells from neuron and immune cell lineages. Harnessing the intra-tumoral heterogeneity of PDN models, we reveal the impact of temozolomide chemotherapy on individual cell states, altering composition of tumors over time in response to treatment. Our data confirms that both patient-derived models recapitulate patient intra-tumoral heterogeneity providing a platform for tumor cell state refined therapeutic studies. Key Points Generation of matched patient-derived neurosphere and organoid models from resected GBM tissue Neurosphere models exhibit greater proliferative signatures Both patient-derived models recapitulate genomic and epigenomic features of the primary tissue Single-nuclei RNA sequencing reveals both models recapitulate intra-tumoral heterogeneity of the primary tissue Neurosphere models enable interrogation of therapeutic responses in the context of heterogeneity Importance of study Patient derived models can be powerful tools when they faithfully recapitulate the tumor tissue from which they are derived. In glioblastoma, patient derived neurospheres (PDN) and organoids (PDO) have both been used in studies, however the differences between these models and the recapitulation of patient heterogeneity remain to be fully characterized. To address this, we performed multi-omic profiling of PDN and PDO models generated from the same tumor tissue. We find that that across a range of data modalities, both model systems exhibit a high level of resemblance to tissue, and critically, maintain heterogeneity and tumor cell composition. The importance of modeling heterogeneity was demonstrated in PDN models, where temozolomide treatment specifically alters the abundance of MES-like and AC-like tumor cells. Our findings demonstrate that neurosphere and organoid models effectively preserve cellular heterogeneity, genomic alterations, methylation signatures and transcriptomic features, both highly suitable to model glioblastoma’s complex cellular landscape.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.01.08.632025
- OA Status
- green
- Cited By
- 2
- References
- 53
- Related Works
- 10
- OpenAlex ID
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All OpenAlex metadata
Raw OpenAlex JSON
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- DOI
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https://doi.org/10.1101/2025.01.08.632025Digital Object Identifier
- Title
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Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneityWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-01-13Full publication date if available
- Authors
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Zachery Moore, Claire Storey, Daniel V. Brown, Adam Valkovic, Montana Spiteri, Jasmine F. Pignatelli, Shannon J. Oliver, A. Fakhri, Katharine J. Drummond, Seth Malinowski, Keith L. Ligon, Oliver M. Sieber, James R. Whittle, Saskia Freytag, Sarah A. BestList of authors in order
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https://doi.org/10.1101/2025.01.08.632025Publisher landing page
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://doi.org/10.1101/2025.01.08.632025Direct OA link when available
- Concepts
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Glioblastoma, Medicine, Computer science, Cancer researchTop concepts (fields/topics) attached by OpenAlex
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2Total citation count in OpenAlex
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2025: 2Per-year citation counts (last 5 years)
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53Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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