Cellular Plasticity during Metastasis: New Insights Provided by Intravital Microscopy

Margarido, Andreia S.; Bornes, Laura; Vennin, Claire; Rheenen, Jacco van

doi:10.1101/cshperspect.a037267

Cited by 11 publications

(8 citation statements)

References 203 publications

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“…Next, we aimed to study the GFAP-modulated cells in an in vivo setting where a functional vasculature is present, and where it is possible to follow tumour progression over time. We used intravital microscopy (IVM), which allows to longitudinally visualise tumour cell behaviour at the single-cell level in a living organism 33 . Per condition, we separately injected www.nature.com/scientificreports/ two H2B-mNeonGreen expressing clones with the most extreme GFAPδ/α ratio (CTL 1, GFAPδ-KO 2, and GFAPα-KO 2 from CRISPR set A, CTL 3, GFAPδ-KO 3, and GFAPα-KO 4 from CRISPR set B) into NOD-Scid IL2Rgnull (NSG) mice.…”

Section: Depletion Of Gfapα Isoform Leads To More Diffuse Tumours In ...mentioning

confidence: 99%

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

Uceda-Castro

Asperen

Vennin

et al. 2022

Sci Rep

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Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAPnetwork lead to specific migratory dynamics and behaviours of gliomas.

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Section: Depletion Of Gfapα Isoform Leads To More Diffuse Tumours In ...mentioning

confidence: 99%

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

Uceda-Castro

Asperen

Vennin

et al. 2022

Sci Rep

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“…Next, we aimed to study the GFAP modulated cells in an in vivo setting where a functional vasculature is present, and where it is possible to follow tumour progression over time. We used intravital microscopy (IVM), which allows to longitudinally visualise tumour cell behaviour at the single-cell level in a living organism 33 . We separately injected two H2B-mNeonGreen expressing clonal lines with the most extreme GFAPδ/α ratio per condition into NOD-Scid IL2Rgnull mice.…”

Section: Depletion Of Gfapα Isoform Leads To More Diffuse Tumours In Vivomentioning

confidence: 99%

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

Asperen

Uceda-Castro

Vennin

et al. 2021

Preprint

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Glioma is the most common form of malignant primary brain tumours in adults. Their highly invasive nature makes the disease incurable to date, emphasizing the importance of better understanding the mechanisms driving glioma invasion. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is characteristic for astrocyte- and neural stem cell-derived gliomas. Glioma malignancy is associated with changes in GFAP alternative splicing, as the canonical isoform GFAPα is downregulated in higher-grade tumours, leading to increased dominance of the GFAPδ isoform in the network. In this study, we used intravital imaging and an ex vivo brain slice invasion model. We show that the GFAPδ and GFAPα isoforms differentially regulate the tumour dynamics of glioma cells. Depletion of either isoform increases the migratory capacity of glioma cells. Remarkably, GFAPδ-depleted cells migrate randomly through the brain tissue, whereas GFAPα-depleted cells show a directionally persistent invasion into the brain parenchyma. This study shows that distinct compositions of the GFAP-network lead to specific migratory dynamics and behaviours of gliomas.

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“…Intravital imaging approaches that allow imaging in both the primary and metastatic sites are now providing key insights into the dynamic temporal and spatial regulation of different stromal cell populations and how they interact with each other and the tumour cells. 43 , 108 , 109 Taken together, the complexity and heterogeneity of signalling within the stroma mean that a pan-treatment targeting individual stromal cells is unlikely to be effective, and that tumour-specific approaches might instead be required. A greater understanding of how the reciprocal communication between immune cells and CAFs sustains a pro-tumorigenic environment provides additional impetus for combining therapies that target CAFs and immune cell functions and opens up exciting opportunities for treating patients with metastatic disease, an important area of unmet clinical need.…”

Section: Discussionmentioning

confidence: 99%

The fibrotic and immune microenvironments as targetable drivers of metastasis

et al. 2020

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Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced metastatic disease are still few and far between. Cancer cells do not exist in isolation: rather, they exist within a complex microenvironment composed of stromal cells and extracellular matrix. Within this tumour microenvironment exists an interplay between the two main stromal cell subtypes, cancer-associated fibroblasts (CAFs) and immune cells, that are important in controlling metastasis. A complex network of paracrine signalling pathways between CAFs, immune cells and tumour cells are involved at multiple stages of the metastatic process, from invasion and intravasation at the primary tumour site to extravasation and colonisation in the metastatic site. Heterogeneity and plasticity within stromal cell populations also contribute to the complexity. Although many of these processes are likely to be common to a number of metastatic sites, we will describe in detail the interplay within the liver, a preferred site of metastasis for many tumours. A greater understanding of these networks provides opportunities for the design of new therapeutic approaches for targeting the metastatic disease.

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Cellular Plasticity during Metastasis: New Insights Provided by Intravital Microscopy

Cited by 11 publications

References 203 publications

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

GFAP splice variants fine-tune glioma cell invasion and tumour dynamics by modulating migration persistence

The fibrotic and immune microenvironments as targetable drivers of metastasis

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