ALDH1A3 contributes to radiation-induced inhibition of self-renewal and promotes proliferative activity of p53-deficient glioblastoma stem cells at the onset of differentiation
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Abstract
ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree
of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regula-
tion of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which
ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for
rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates
glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often
unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3
in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by
modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration
of the impacts of inherent plasticity and proliferative changes associated with transitions between
cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of
glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition
of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects
ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting
glioblastoma growth under radiation treatment.