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Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation
Ling He1,2, Daria Azizad3, Kruttika Bhat1
1Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095.
Abstract:
Glioblastoma (GBM) is the deadliest brain cancer in adults, and all patients succumb to the tumor. While surgery followed by chemoradiotherapy delays disease progression, these treatments do not lead to tumor control, and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution, and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single-cell RNA-seq. Effects on glioma stem cells (GSCs) were studied in extreme limiting dilution assays, and the effects on median survival were studied in both syngeneic and PDOX mouse models of GBM. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation, and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of GSCs and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.
Insights
This study shows that combining forskolin with radiation therapy can reprogram deadly brain cancer cells (glioblastoma) into neuron-like cells, significantly improving survival in mouse models.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Cellular Differentiation
Background:
- Glioblastoma (GBM) is an aggressive brain cancer with poor prognosis.
- Current treatments like surgery, chemoradiotherapy, and targeted therapies offer limited survival benefits.
- Glioma stem cells (GSCs) are implicated in tumor recurrence and treatment resistance.
Purpose of the Study:
- To investigate the potential of combining forskolin, an adenylcyclase activator, with radiation to alter glioma cell fate.
- To evaluate the effects of this combined treatment on cellular markers, proliferation, and survival in GBM models.
Main Methods:
- Utilized bulk and single-cell RNA sequencing (scRNA-seq) to analyze gene expression and cell population changes.
- Assessed effects on neuronal marker expression, cell cycle, and proliferation.
- Studied impact on glioma stem cells (GSCs) using extreme limiting dilution assays.
- Evaluated median survival in syngeneic and patient-derived xenograft (PDOX) mouse models of GBM.
Main Results:
- The combined forskolin and radiation treatment induced neuronal marker expression in glioma cells.
- Reduced cell proliferation and altered gene expression profiles were observed.
- scRNA-seq indicated a shift towards microglia- and neuron-like phenotypes.
- In vivo studies demonstrated a reduction in GSCs and prolonged median survival.
Conclusions:
- Reprogramming glioma cells towards a neuronal fate using forskolin and radiation is a viable therapeutic strategy.
- This approach shows promise for overcoming treatment resistance and improving outcomes in glioblastoma.
- Further clinical investigation of this differentiation therapy combination is warranted.
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