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Published on: November 28, 2015
Yes and PI3K bind CD95 to signal invasion of glioblastoma
Susanne Kleber1, Ignacio Sancho-Martinez, Benedict Wiestler
1Molecular Neurobiology Group, German Cancer Research Center (DKFZ), INF 581, 69120 Heidelberg, Germany.
Abstract:
Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.
Insights
Glioblastoma invasion is driven by CD95 Ligand signaling, activating PI3K and matrix metalloproteinases. Neutralizing CD95 significantly reduced glioma cell invasion in vivo, revealing a key therapeutic target.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer research
Background:
- Glioblastoma multiforme (GBM) invasion into brain tissue hinders curative therapies.
- Understanding the molecular mechanisms of glioma cell infiltration is critical for developing effective treatments.
Purpose of the Study:
- To elucidate the mechanism regulating glioma infiltration.
- To investigate the role of CD95 Ligand in GBM invasion.
- To identify potential therapeutic targets for inhibiting GBM spread.
Main Methods:
- Studied tumor-brain tissue interactions to induce CD95 Ligand expression.
- Investigated signaling pathways (Src family, PI3K, GSK-3beta) activated by CD95.
- Assessed matrix metalloproteinase expression.
- Utilized a murine syngeneic model of intracranial GBM to test CD95 neutralization.
Main Results:
- Tumor interaction with brain tissue upregulates CD95 Ligand.
- CD95 Ligand binding to CD95 recruits Yes and PI3K, activating invasion via GSK-3beta and matrix metalloproteinases.
- Neutralization of CD95 activity significantly reduced glioma cell invasion in an in vivo GBM model.
Conclusions:
- CD95 acts as an activator of phosphatidylinositol 3-kinase (PI3K).
- CD95 is a crucial trigger for basal glioblastoma invasion in vivo.
- Targeting CD95 represents a promising therapeutic strategy against GBM infiltration.
