Differential transformation capacity of neuro-glial progenitors during development

Abstract

Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox-mediated and Tet-regulated expression to drive K-ras G12D expression in neuro-glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-ras G12D -induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-ras G12D expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation. mouse models | temporal specification | lineage | differentiation

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

“…These results are in accordance with the recent work of Munoz et al [97] regarding the differential transformation capacity of neuro-glial progenitors during development. In this study, a tumorigenic process was induced and initiated by an oncogenic stimulus (Ras-pathway activation) in neuro-glial progenitors populations at different developmental stages.…”

Cell of Origin for Malignant Gliomas and Its Implication in Therapeutic Development

“…It was found that introduction of p53 and NF1 mutations into NSCs led to consistent glioma formation (Zhu et al 2005). Another study found that induced expression of KRAS G12D alone in embryonic radial glia was able to induce gliomas, however cooperating loss of p53 was required for postnatal gliomagenesis, indicating that cells in a less differentiated more stem-like state are more readily transformed (Munoz et al 2013a high-grade gliomas, convincingly demonstrating that NSCs are susceptible to gliomagenic transformation.…”

A Nuclear Role for miR-9 and Argonaute Proteins in Balancing Quiescent and Activated Neural Stem Cell States

“…Interestingly, a recent study revealed a progressive change in the expression of cell-cycle regulators in BLBP-positive RG during post-natal stages in mice, directly influencing the competence of these cells to be transformed by oncogenes (Muñoz et al., 2013). Moreover, a change in microRNAs signature occurs in muscle satellite stem cells between juvenile and adult stages and correlates with a modification of cell-cycle dynamics (Sato et al., 2014).…”