Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
26 02 2020
26 02 2020
Historique:
received:
17
06
2019
accepted:
04
12
2019
revised:
03
12
2019
entrez:
28
2
2020
pubmed:
28
2
2020
medline:
10
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32102991
doi: 10.1038/s41419-020-2342-2
pii: 10.1038/s41419-020-2342-2
pmc: PMC7044427
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
152Subventions
Organisme : NCI NIH HHS
ID : T32 CA059366
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR026820
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007250
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA198254
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103418
Pays : United States
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