Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice
Dinorah Friedmann-Morvinski1, Eric A Bushong, Eugene Ke
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Abstract:
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Here we show that gliomas can originate from differentiated cells in the central nervous system (CNS), including cortical neurons. Transduction by oncogenic lentiviral vectors of neural stem cells (NSCs), astrocytes, or even mature neurons in the brains of mice can give rise to malignant gliomas. All the tumors, irrespective of the site of lentiviral vector injection (the initiating population), shared common features of high expression of stem or progenitor markers and low expression of differentiation markers. Microarray analysis revealed that tumors of astrocytic and neuronal origin match the mesenchymal GBM subtype. We propose that most differentiated cells in the CNS upon defined genetic alterations undergo dedifferentiation to generate a NSC or progenitor state to initiate and maintain the tumor progression, as well as to give rise to the heterogeneous populations observed in malignant gliomas.
Insights
Malignant gliomas, including glioblastoma, can arise from mature brain cells like neurons. Genetic changes cause these cells to dedifferentiate into stem-like cells, driving tumor growth and diversity.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Stem Cell Research
Background:
- Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor.
- The cellular origin of GBM remains a critical question in neuro-oncology.
Purpose of the Study:
- To investigate whether differentiated central nervous system (CNS) cells can initiate glioma formation.
- To characterize the cellular state and molecular subtype of experimentally induced gliomas.
Main Methods:
- Oncogenic lentiviral vectors were used to transduce neural stem cells (NSCs), astrocytes, and mature neurons in mouse brains.
- Tumorigenesis was monitored, and resulting gliomas were analyzed for stem/progenitor and differentiation markers.
- Microarray analysis was performed to determine molecular subtypes.
Main Results:
- Gliomas were successfully induced from NSCs, astrocytes, and mature neurons.
- All induced tumors exhibited high expression of stem/progenitor markers and low differentiation markers.
- Tumors of astrocytic and neuronal origin were classified as the mesenchymal GBM subtype.
Conclusions:
- Differentiated CNS cells, including neurons, can dedifferentiate into a neural stem cell or progenitor state to initiate malignant gliomas.
- This dedifferentiation process is crucial for tumor initiation, progression, and the observed cellular heterogeneity in gliomas.
- Findings suggest a novel mechanism for glioma development involving cellular plasticity in the adult CNS.
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