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Updated: Aug 28, 2025
Maintaining Human Glioblastoma Cellular Diversity Ex vivo using Three-Dimensional Organoid Culture
Published on: August 25, 2022
SerpinB3 drives cancer stem cell survival in glioblastoma
Adam Lauko1, Josephine Volovetz2, Soumya M Turaga3
1Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA; Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Abstract:
Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.
Insights
SerpinB3, a protein inhibiting cell death, is crucial for glioblastoma cancer stem cell survival and tumor growth. Targeting SerpinB3 enhances glioblastoma therapy efficacy against resistant stem cells.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Molecular Biology
Background:
- Glioblastoma (GBM) recurrence is driven by cancer stem cells (CSCs).
- Mechanisms of CSC resistance, particularly cell death inhibition, remain unclear.
- Junctional adhesion molecule-A (JAM-A) is implicated in CSC maintenance.
Purpose of the Study:
- To elucidate downstream signaling networks involved in CSC resistance.
- To identify specific molecular targets for overcoming GBM therapeutic resistance.
Main Methods:
- Genetic depletion approaches (e.g., knockdown) were used to investigate SerpinB3 function.
- Analysis of CSC maintenance, survival, tumor growth, and pathway activation.
- Assessment of apoptosis and susceptibility to radiation therapy.
Main Results:
- SerpinB3 is essential for glioblastoma cancer stem cell maintenance, survival, and tumor growth.
- SerpinB3 knockdown increased apoptosis and sensitivity to radiation therapy.
- SerpinB3 buffers cathepsin L-mediated cell death, which is potentiated by radiation.
Conclusions:
- SerpinB3 represents a critical GBM CSC-specific survival mechanism.
- Targeting SerpinB3 can enhance the efficacy of radiation therapy against resistant GBM CSCs.
- SerpinB3 is a potential therapeutic target to overcome glioblastoma recurrence.
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