Related Experiment Video
Updated: Mar 19, 2026
Live-Cell Imaging Assays to Study Glioblastoma Brain Tumor Stem Cell Migration and Invasion
Published on: August 29, 2018
γ-Secretase inhibitor-resistant glioblastoma stem cells require RBPJ to propagate
Abstract:
Targeting glioblastoma stem cells with γ-secretase inhibitors (GSIs) disrupts the Notch pathway and has shown some benefit in both pre-clinical models and in patients during phase I/II clinical trials. However, it is largely unknown why some glioblastoma (GBM) does not respond to GSI treatment. In this issue of the JCI, Xie et al. determined that GSI-resistant brain tumor-initiating cells (BTICs) from GBM express a higher level of the gene RBPJ, which encodes a mediator of canonical Notch signaling, compared to non-BTICs. Knockdown of RBPJ in BTICs decreased propagation in vitro and in vivo by inducing apoptosis. Interestingly, RBPJ was shown to regulate a different transcription program than Notch in BTICs by binding CDK9, thereby affecting Pol II-regulated transcript elongation. Targeting CDK9 or c-MYC, an upstream regulator of RBPJ, with small molecules also decreased BTIC propagation, and prolonged survival in mice bearing orthotopic GBM xenografts. This study not only provides a mechanism for GSI treatment resistance, but also identifies two potential therapeutic strategies to target GSI-resistant BTICs.
Insights
Glioblastoma stem cells resistant to Notch pathway inhibitors show high RBPJ levels. Targeting RBPJ or CDK9 may overcome this resistance, offering new glioblastoma treatment strategies.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer research
Background:
- Glioblastoma stem cells (GSCs) are targeted with gamma-secretase inhibitors (GSIs) to disrupt the Notch pathway.
- While GSIs show some efficacy, resistance mechanisms in glioblastoma (GBM) remain largely unknown.
Purpose of the Study:
- To elucidate the mechanism behind GSI resistance in glioblastoma.
- To identify novel therapeutic targets for GSI-resistant glioblastoma stem cells.
Main Methods:
- Analysis of RBPJ gene expression in GSI-resistant versus non-resistant glioblastoma cells.
- Investigating the role of RBPJ in GSI-resistant brain tumor-initiating cells (BTICs) through knockdown experiments.
- Examining the interaction of RBPJ with CDK9 and its effect on transcription.
- Evaluating the efficacy of targeting CDK9 or c-MYC in preclinical GBM models.
Main Results:
- GSI-resistant BTICs exhibit significantly higher RBPJ expression compared to non-BTICs.
- RBPJ knockdown in BTICs inhibits proliferation and induces apoptosis in vitro and in vivo.
- RBPJ regulates distinct transcriptional programs in BTICs by interacting with CDK9, influencing RNA polymerase II elongation.
- Targeting CDK9 or c-MYC with small molecules reduces BTIC propagation and improves survival in GBM xenografts.
Conclusions:
- RBPJ is a key mediator of GSI resistance in glioblastoma stem cells.
- RBPJ's function in resistance involves regulating transcription via CDK9, independent of canonical Notch signaling.
- Targeting RBPJ, CDK9, or c-MYC presents promising therapeutic strategies for overcoming GSI resistance in glioblastoma.
More Related Videos
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:38The Ras Gene
Ras is a...
01:23Negative Regulator Molecules
02:40Cancer Stem Cells and Tumor Maintenance
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...