Related Experiment Video
Updated: May 3, 2026
Translational Orthotopic Models of Glioblastoma Multiforme
Published on: February 17, 2023
EFEMP1 induces γ-secretase/Notch-mediated temozolomide resistance in glioblastoma
Lotte Hiddingh1, Bakhos A Tannous, Jian Teng
1Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
Abstract:
Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including γ-secretase-mediated activation of the Notch pathway. We show that inhibition of γ-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ-resistance in glioblastoma.
Insights
EFEMP1 protein promotes glioblastoma resistance to temozolomide (TMZ) chemotherapy. Inhibiting EFEMP1 or its associated Notch pathway may re-sensitize tumors to TMZ, offering new therapeutic strategies for brain cancer.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer research
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Temozolomide (TMZ) is the standard chemotherapy, but resistance is a significant challenge.
Purpose of the Study:
- To identify molecular factors contributing to TMZ resistance in glioblastoma.
- To explore EFEMP1 as a potential therapeutic target for overcoming TMZ resistance.
Main Methods:
- Engineered TMZ-resistant glioblastoma cell lines.
- Performed gene expression analysis to identify key proteins.
- Utilized gene silencing and overexpression techniques.
- Investigated the role of EFEMP1 in Notch pathway signaling.
- Tested γ-secretase inhibitor RO4929097 in vitro and in vivo.
Main Results:
- EFEMP1 expression was significantly associated with TMZ resistance.
- Silencing EFEMP1 decreased glioblastoma cell survival after TMZ treatment.
- Overexpressing EFEMP1 induced TMZ resistance.
- EFEMP1 influences TMZ resistance via the Notch pathway.
- Inhibiting γ-secretase partially sensitized glioblastoma to TMZ.
- Higher EFEMP1 levels correlated with poorer survival in TMZ-treated patients.
Conclusions:
- EFEMP1 is a key mediator of TMZ resistance in glioblastoma.
- Targeting EFEMP1 or the Notch pathway presents a promising strategy to enhance TMZ efficacy.
- EFEMP1 represents a potential therapeutic target for glioblastoma treatment.
