Ricerc@Sapienza

Glioblastomas (GBM) are the most aggressive form of primary brain tumors in humans.
A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of
an undierentiated cell population of defined Glioblastoma Stem cells (GSCs) was reported. Increased
expression of anti-apoptotic and chemo-resistance genes in GCSs subpopulation favors their high
resistance to a broad spectrum of drugs. Our previous studies showed the ability of M2 muscarinic
receptors to negatively modulate the cell growth in GBM cell lines and in the GSCs. The aim of
this study was to better characterize the inhibitory eects of M2 receptors on cell proliferation
and survival in GSCs and investigate the molecular mechanisms underlying the M2-mediated cell
proliferation arrest and decreased survival. Moreover, we also evaluated the ability of M2 receptors to
interfere with Notch1 and EGFR pathways, whose activation promotes GSCs proliferation. Our data
demonstrate that M2 receptors activation impairs cell cycle progression and survival in the primary
GSC lines analyzed (GB7 and GB8). Moreover, we also demonstrated the ability of M2 receptor to
inhibit Notch1 and EGFR expression, highlighting a molecular interaction between M2 receptor and
the Notch-1/EGFR pathways also in GSCs