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Reprogramming the fate of human glioma cells to impede brain tumor development
11] Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA [2] Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Abstract:
Malignant gliomas, the most common solid tumors in the central nervous system, are essentially incurable due to their rapid growth and very invasive nature. One potential approach to eradicating glioma cells is to force these cells to undergo terminal differentiation and, in the process, to irreversible postmitotic arrest. Here, we show that neurogenin 2 (NGN2, also known as NEUROG2) synergizes with sex-determining region Y-box 11 (SOX11) to very efficiently convert human glioma cells to terminally differentiated neuron-like cells in both cell culture and adult mouse brains. These cells exhibit neuronal morphology, marker expression, and electrophysiological properties. The conversion process is accompanied by cell cycle exit, which dramatically inhibits glioma cell proliferation and tumor development after orthotopic transplantation. Most importantly, intracranial injection of NGN2- and SOX11-expressing virus into the tumor mass also curtails glioma growth and significantly improves survival of tumor-bearing mice. Taken together, this study shows a simple and highly efficient strategy for reprogramming malignant glioma cells into postmitotic cells, which might be a promising therapeutic approach for brain tumors.
Insights
This study demonstrates that combining neurogenin 2 (NGN2) and sex-determining region Y-box 11 (SOX11) effectively converts malignant glioma cells into neuron-like cells, inhibiting tumor growth and improving survival.
Area of Science:
- Neuroscience
- Oncology
- Cell Biology
Background:
- Malignant gliomas are aggressive brain tumors with poor prognoses.
- Current treatments are limited due to glioma invasiveness and rapid proliferation.
- Forcing glioma cell differentiation offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the potential of neurogenin 2 (NGN2) and sex-determining region Y-box 11 (SOX11) in reprogramming glioma cells.
- To evaluate the efficacy of this reprogramming strategy in inhibiting glioma growth and progression.
Main Methods:
- Utilized a combination of NGN2 and SOX11 to induce differentiation in human glioma cells in vitro and in vivo.
- Assessed neuronal morphology, marker expression, and electrophysiological properties of converted cells.
- Evaluated the impact of reprogramming on glioma cell proliferation, tumor development, and survival in mouse models.
Main Results:
- NGN2 and SOX11 synergistically converted human glioma cells into neuron-like cells with neuronal characteristics.
- The conversion process led to cell cycle exit, significantly inhibiting glioma proliferation and tumor growth.
- Intracranial delivery of NGN2 and SOX11 reduced tumor burden and improved survival in tumor-bearing mice.
Conclusions:
- Reprogramming malignant glioma cells into terminally differentiated neurons using NGN2 and SOX11 is a highly efficient strategy.
- This approach shows promise as a novel therapeutic strategy for treating brain tumors.
