Adaptive adhesion systems mediate glioma cell invasion in complex environments

Gritsenko, Pavlo G.; Friedl, Peter

doi:10.1242/jcs.216382

Cited by 34 publications

(33 citation statements)

References 79 publications

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“…The development of glioma is a complex biological process that involves multiple mechanisms and factors (10,11). Numerous tumor suppressor genes, oncogenes, and growth factors have been confirmed to be involved in glioma progression (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

Jin

Liu

et al. 2020

Front. Oncol.

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Background: Glioma is the most common malignant tumor of the central nervous system, and often displays invasive growth. Recently, circular RNA (circRNA), which is a novel non-coding type of RNA, has been shown to play a vital role in glioma tumorigenesis. However, the functions and mechanism of lipocalin-2 (Lcn2)-derived circular RNA (hsa_circ_0088732) in glioma progression remain unclear. Methods: We evaluated hsa_circ_0088732 expression by fluorescence in situ hybridization (FISH), Sanger sequencing, and PCR assays. Cell apoptosis was evaluated by flow cytometry and Hoechst 33258 staining. Transwell migration and invasion assays were performed to measure cell metastasis and viability. In addition, the target miRNA of hsa_circ_0088732 and the target gene of miR-661 were predicted by a bioinformatics analysis, and the interactions were verified by dual-luciferase reporter assays. RAB3D expression was analyzed by an immunochemistry assay, and E-cadherin, N-cadherin, and vimentin protein expression were examined by western blot assays. A mouse xenograft model was developed and used to analyze the effects of hsa_circ_0088732 on glioma growth in vivo. Results: We verified that hsa_circ_0088732 is circular and highly expressed in glioma tissues. Knockdown of hsa_circ_0088732 induced glioma cell apoptosis and inhibited glioma cell migration, invasion, and epithelial-mesenchymal transition (EMT). We found that hsa_circ_0088732 negatively regulated miR-661 by targeting miR-661, and RAB3D was a target gene of miR-661. In addition, inhibition of miR-661 promoted glioma cell metastasis and suppressed cell apoptosis. Knockdown of RAB3D induced cell apoptosis and suppressed cell metastasis. Moreover, hsa_circ_0088732 accelerated glioma progression through its effects on the miR-661/RAB3D axis. Finally, results from a mouse xenograft model confirmed that knockdown of hsa_circ_0088732 induced miR-661 expression, resulting in suppression of RAB3D expression and inhibition of tumor growth in vivo. Jin et al. hsa_circ_0088732 Acts as an Oncogene in Glioma Conclusion: We demonstrated that hsa_circ_0088732 facilitated glioma progression by sponging miR-661 to increase RAB3D expression. This study provides a theoretical basis for understanding the development and occurrence of glioma, as well as for the development of targeted drugs.

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Section: Introductionmentioning

confidence: 99%

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

Jin

Liu

et al. 2020

Front. Oncol.

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“…The mode of migration may be critical for how well tumor cells, including those in GBM, are able to invade the surrounding tissue and disseminate. Several recent studies found that GBM cells can migrate collectively 26,27 , although whether GBM CSCs specifically use this type of migration is an open question. Our data indicate that a variety of patient-derived GBM CSC models can move in small to large collectives away from tumor spheres plated on Geltrex, although CSCs can also migrate individually and as mixtures of single cells and collectives.…”

Section: Discussionmentioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Volovetz

Berezovsky

Alban

et al. 2019

Preprint

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Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development.Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. RAP1A

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“…The sensitivity of U87 cells to cilengitide-induced detachment has been shown to be dependent on the composition of the ECM, with cells cultured on collagen-coated plates resisting detachment (34,46). Gritsenko and Friedl have recently demonstrated that αV and β1 integrins represent the primary adhesion systems for glioma cell migration in different migration models (spheroids and organotypic brain slices) (35). However, P R E P R I N T when they compared the same integrin interference strategy in the different models, they observed a variation in the contribution of integrin-dependent glioma invasion.…”

Section: Drug Effects On Cell Invasion Versus Cell Migrationmentioning

confidence: 99%

4D imaging and analysis of multicellular tumour spheroid cell migration and invasion

Richards

Mason

Kelly

et al. 2018

Preprint

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Studying and characterising tumour cell migration is critical for understanding disease progression and for assessing drug efficacy. Whilst tumour cell migration occurs fundamentally in 3 spatial dimensions (3D), for practical reasons, most migration studies to date have performed analysis in 2D. Here we imaged live multicellular tumour spheroids with lightsheet fluorescence microscopy to determine cellular migration and invasion in 3D over time (4D). We focused on glioblastoma, which are aggressive brain tumours, where cell invasion into the surrounding normal brain remains a major clinical challenge. We developed a workflow for analysing complex 3D cell movement, taking into account migration within the spheroid as well as invasion into the surrounding matrix. This provided metrics characterising cell motion, which we used to evaluate the efficacy of chemotherapeutics on invasion. These rich datasets open avenues for further studies on drug efficacy, microenvironment composition, as well as collective cell migration and metastatic potential. LSFM | SPIM | Lightsheet Microscopy | Cell Tracking | Invasion | Spheroids | Glioblastoma | 3DCorrespondence: violaine@liverpool.ac.uk

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Adaptive adhesion systems mediate glioma cell invasion in complex environments

Cited by 34 publications

References 79 publications

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

4D imaging and analysis of multicellular tumour spheroid cell migration and invasion

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