Abstract
RAS activation and p53 loss induce dedifferentiation of mature cells into tumor-initiating cells.
Major finding: RAS activation and p53 loss induce dedifferentiation of mature cells into tumor-initiating cells.
Clinical relevance: Astrocyte and neuron-derived tumors resemble the mesenchymal GBM subtype.
Impact: Brain cell plasticity, not a distinct population of cancer stem cells, may underlie gliomagenesis.
Genomic analyses have facilitated the classification of glioblastoma multiforme (GBM) into several molecular subtypes, but our understanding of the etiology of this heterogeneous group of tumors remains extremely limited. The identification of tumor-initiating cells expressing stem and progenitor cell markers in GBM has led to the theory that cells with intrinsic stem-like properties underlie GBM initiation and recurrence. However, Friedmann-Morvinski and colleagues report that dedifferentiation of mature cells can also lead to GBM formation. Simultaneous p53 inactivation and activation of the RAS pathway, either by neurofibromin 1 (NF1) inactivation or mutant HRAS expression, in the neurons or astrocytes of transgenic mice using Cre recombinase-inducible lentiviral vectors led to the formation of high-grade gliomas regardless of the site of injection. Limiting dilutions of primary cortical neurons or astrocytes that were lentivirally transduced in vitro and transplanted into recipient mice also form ed high-grade gliomas that expressed high levels of neural progenitor markers, further indicating that terminally differentiated cells could undergo transformation and act as tumor-initiating cells. Consistent with a paradigm in which oncogenic insults lead mature cells to acquire the capacity to dedifferentiate into neuroprogenitor-like pluripotent cells, primary cortical neurons and astrocytes transduced with both mutant HRAS and p53 short hairpin RNA changed morphology and formed neurosphere-like structures, whereas untransduced cells, cells only lacking p53, or cells only expressing mutant HRAS remained astrocytes. Of note, the expression signatures of the neuron- and astrocyte-derived gliomas resembled those of human mesenchymal-subtype GBMs, in which inactivating mutations of NF1 and TP53 are sometimes found, suggesting that a similar phenomenon may occur in human brain tumors.
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