Glioblastoma (GBM) is one of the most aggressive types of cancer with limited
therapeutic options and unfavorable prognosis. Stemness and non-classical
epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from
normal to neoplastic states as well as resistance of tumor clones to current
therapies. Therefore, identification of ligand/receptor systems maintaining
this privileged state is needed to devise efficient cancer therapies. In this
study, we show that the expression of CD95 associates with stemness and EMT
features in GBM tumors and cells and serves as a prognostic biomarker. CD95
expression increases in tumors and with tumor relapse as compared with non-
tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death
domain is required for maintenance of EMT-related transcripts. A combination
of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically
abrogates tumor sphere formation. This study molecularly dissects the role of
CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM
therapy