Fishing for Contact: Modeling Perivascular Glioma Invasion in the Zebrafish Brain

Umans, Robyn A.; Kate, Mattie ten; Pollock, Carolyn; Sontheimer, Harald

doi:10.1021/acsptsci.0c00129

Cited by 12 publications

(6 citation statements)

References 49 publications

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“…We previously demonstrated in a model of perivascular glioma invasion, that glial-derived tumor cells associate with the developing zebrafish brain vasculature ( Umans et al, 2020 ). However, we wanted to assess whether non-malignant glia would similarly contact zebrafish brain vessels.…”

Section: Resultsmentioning

confidence: 99%

Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development

Umans

Pollock

Mills

et al. 2021

Front. Cell Dev. Biol.

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An emerging area of interest in Neuroscience is the cellular relationship between glia and blood vessels, as many of the presumptive support roles of glia require an association with the vasculature. These interactions are best studied in vivo and great strides have been made using mice to longitudinally image glial-vascular interactions. However, these methods are cumbersome for developmental studies, which could benefit from a more accessible system. Zebrafish (Danio rerio) are genetically tractable vertebrates, and given their translucency, are readily amenable for daily live imaging studies. We set out to examine whether zebrafish glia have conserved traits with mammalian glia regarding their ability to interact with and maintain the developing brain vasculature. We utilized transgenic zebrafish strains in which oligodendrocyte transcription factor 2 (olig2) and glial fibrillary acidic protein (gfap) identify different glial populations in the zebrafish brain and document their corresponding relationship with brain blood vessels. Our results demonstrate that olig2+ and gfap+ zebrafish glia have distinct lineages and each interact with brain vessels as previously observed in mouse brain. Additionally, we manipulated these relationships through pharmacological and genetic approaches to distinguish the roles of these cell types during blood vessel development. olig2+ glia use blood vessels as a pathway during their migration and Wnt signaling inhibition decreases their single-cell vessel co-option. By contrast, the ablation of gfap+ glia at the beginning of CNS angiogenesis impairs vessel development through a reduction in Vascular endothelial growth factor (Vegf), supporting a role for gfap+ glia during new brain vessel formation in zebrafish. This data suggests that zebrafish glia, akin to mammalian glia, have different lineages that show diverse interactions with blood vessels, and are a suitable model for elucidating glial-vascular relationships during vertebrate brain development.

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Section: Resultsmentioning

confidence: 99%

Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development

Umans

Pollock

Mills

et al. 2021

Front. Cell Dev. Biol.

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“…They have proven highly suited for xenotransplantation of human tumor cells, and GBM tumor cells in particular, due to high similarity with the human brain structure (Reimunde et al, 2021). Zebrafish xenograft models are used extensively to study GBM initiation, progression, migration, vasculature and invasion (Pudelko et al, 2018;Pan et al, 2020;Vittori et al, 2016;Umans et al, 2021;Mazzolini et al, 2022). Hamilton et al studied the interaction between microglia and transplanted GBM cell lines U87 and U251.…”

Section: Discussionmentioning

confidence: 99%

Single-cell profiling and zebrafish avatars revealLGALS1as immunomodulating target in glioblastoma

Finotto

Cole

Giese

et al. 2023

Preprint

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Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs - features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets.

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“…They have proven highly suited for xenotransplantation of human tumor cells, and GBM tumor cells in particular, due to high similarity with the human brain structure (Reimunde et al , 2021 ). Zebrafish xenograft models are used extensively to study GBM initiation, progression, migration, vasculature and invasion (Vittori et al , 2016 ; Pudelko et al , 2018 ; Pan et al , 2020 ; Umans et al , 2021 ; Mazzolini et al , 2022 ). Hamilton et al ( 2016 ) studied the interaction between microglia and transplanted GBM cell lines U87 and U251.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma

Finotto,

Cole,

Giese

et al. 2023

EMBO Mol Med

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Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM‐associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient‐derived GBM stem cell cultures and combined single‐cell RNA sequencing of GAM‐GBM co‐cultures and real‐time in vivo monitoring of GAM‐GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM‐induced GAM polarization and the ability to attract and activate GAMs—features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock‐out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM‐GBM interactions can be studied in a clinically relevant way using co‐cultures and avatar models, while offering new opportunities to identify promising immune‐modulating targets.

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Fishing for Contact: Modeling Perivascular Glioma Invasion in the Zebrafish Brain

Cited by 12 publications

References 49 publications

Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development

Using Zebrafish to Elucidate Glial-Vascular Interactions During CNS Development

Single-cell profiling and zebrafish avatars revealLGALS1as immunomodulating target in glioblastoma

Single‐cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma

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