In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Abstract

Significance Glioblastoma is one of the most radio-resistant tumors, and the mechanisms of radioresistance are intensely studied. Here, we use a mouse model of proneural glioma to evaluate in vivo radiation-induced gene expression regulation at both the translational and transcriptional levels. We found that p53 and E2F are major regulators of the in vivo radiation response, and that there is little contribution from translational regulation, in contrast to previous in vitro reports. We also found that radiation induces a rapid shift in subtype from proneural to mesenchymal, which may have important implications for attempts to tailor targeted therapy regimens to tumor subtype.

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

“…Second, the efficient metabolic inhibition of tumor growth triggered by the mesenchymal GLN High cells is of particular interest because it has been shown that this subtype is the most resistant to therapy (3,36). Furthermore, a recent study has shown that radiation promotes a molecular shift from the proneural to the mesenchymal subtype (40). In this .…”

STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma

“…Those findings suggested that STAT3 activation is involved in glioma tumorigenesis and tumor aggressiveness. Furthermore, in vivo study of glioma molecular response to ionizing radiation showed a time-dependent increase in pSTAT3-Y705 expressing tumor cells in a spontaneous GBM model generated in mice (23).…”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…Mouse GSCs can overcome the damage of repeated irradiation through gradual activation of IGF1R-dependent resistance pathways (55), and repeated chemoand radiotherapies render human GSCs more aggressive and enrich their stem cell features (63,140). GBM recurrence is also associated with a transition from glial to mesenchymal phenotype and is related to poor outcome (141,142). Autophagy is another player in adaptive radioresistance mechanisms in GSCs (117).…”