Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion.

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License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_87AB14679AE7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion.
Journal
Neoplasia
Author(s)
Schönholzer M.T., Migliavacca J., Alvarez E., Santhana Kumar K., Neve A., Gries A., Ma M., Grotzer M.A., Baumgartner M.
ISSN
1476-5586 (Electronic)
ISSN-L
1476-5586
Publication state
Published
Issued date
10/2020
Peer-reviewed
Oui
Volume
22
Number
10
Pages
470-483
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Aberrantly activated kinase signaling pathways drive invasion and dissemination in medulloblastoma (MB). A majority of tumor-promoting kinase signaling pathways feed into the mitogen-activated protein kinase (MAPK) extracellular regulated kinase (ERK1/2) pathway. The activation status of ERK1/2 during invasion of MB cells is not known and its implication in invasion control unclear. We established a synthetic kinase activation relocation sensor (SKARS) for the MAPK ERK1/2 pathway in MB cells for real-time measuring of drug response. We used 3D invasion assays and organotypic cerebellum slice culture to test drug effects in a physiologically relevant tissue environment. We found that hepatocyte growth factor (HGF), epidermal growth factor (EGF), or basic fibroblast growth factor (bFGF) caused rapid nuclear ERK1/2 activation in MB cells, which persisted for several hours. Concomitant treatment with the BCR/ABL kinase inhibitor dasatinib completely repressed nuclear ERK1/2 activity induced by HGF and EGF but not by bFGF. Increased nuclear ERK1/2 activity correlated positively with speed of invasion. Dasatinib blocked ERK-associated invasion in the majority of cells, but we also observed fast-invading cells with low ERK1/2 activity. These ERK1/2-low, fast-moving cells displayed a rounded morphology, while ERK-high fast-moving cells displayed a mesenchymal morphology. Dasatinib effectively blocked EGF-induced proliferation while it only moderately repressed tissue invasion, indicating that a subset of cells may evade invasion repression by dasatinib through non-mesenchymal motility. Thus, growth factor-induced nuclear activation of ERK1/2 is associated with mesenchymal motility and proliferation in MB cells and can be blocked with the BCR/ABL kinase inhibitor dasatinib.
Keywords
Antineoplastic Agents/pharmacology, Apoptosis, Cell Movement, Cell Proliferation, Cerebellar Neoplasms/drug therapy, Cerebellar Neoplasms/metabolism, Cerebellar Neoplasms/pathology, Dasatinib/pharmacology, Gene Expression Regulation, Neoplastic/drug effects, Humans, MAP Kinase Signaling System/drug effects, Medulloblastoma/drug therapy, Medulloblastoma/metabolism, Medulloblastoma/pathology, Mitogen-Activated Protein Kinases/genetics, Mitogen-Activated Protein Kinases/metabolism, Neoplasm Invasiveness, Tumor Cells, Cultured, Cell migration, Cerebellum slice culture, Fluorescent biosensor, Live cell imaging, Medulloblastoma, Nuclear ERK1/2 activation sensor
Pubmed
Web of science
Open Access
Yes
Create date
03/09/2020 10:51
Last modification date
09/08/2024 15:02
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