CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells

M Drachsler; S Kleber; A Mateos; K Volk; N Mohr; S Chen; B Cirovic; J Tüttenberg; C Gieffers; J Sykora; C R Wirtz; W Mueller; M Synowitz; A Martin-Villalba

doi:10.1038/cddis.2016.102

CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells

Cell Death Dis. 2016 Apr 28;7(4):e2209. doi: 10.1038/cddis.2016.102.

Authors

M Drachsler¹, S Kleber¹, A Mateos¹, K Volk¹, N Mohr¹, S Chen¹, B Cirovic², J Tüttenberg³, C Gieffers⁴, J Sykora⁴, C R Wirtz⁵, W Mueller⁶, M Synowitz^{7

8}, A Martin-Villalba¹

Affiliations

¹ Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
² Department of Cell Differentiation and Tumorigenesis, Max Delbrück Center, Berlin 13125, Germany.
³ Department of Neurosurgery, Clinical Center Idar-Oberstein, Idar-Oberstein 55743, Germany.
⁴ Apogenix GmbH, Heidelberg 69120, Germany.
⁵ Department of Neurosurgery, University Hospital Ulm, Günzburg 89312, Germany.
⁶ Department of Neuropathology, University Hospital Leipzig, Leipzig 04103, Germany.
⁷ Department of Neurosurgery, Charité, University Medicine Berlin, Berlin 13353, Germany.
⁸ Department of Neurosurgery, Campus Kiel, Kiel 24105, Germany.

Abstract

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.

MeSH terms

Antineoplastic Agents, Alkylating / pharmacology
Brain Neoplasms / classification
Brain Neoplasms / genetics*
Brain Neoplasms / mortality
Brain Neoplasms / pathology
Class Ia Phosphatidylinositol 3-Kinase / genetics
Class Ia Phosphatidylinositol 3-Kinase / metabolism
Dacarbazine / analogs & derivatives
Dacarbazine / pharmacology
Drug Combinations
Drug Synergism
Epithelial-Mesenchymal Transition / genetics*
Gene Expression Regulation, Neoplastic*
Glioblastoma / classification
Glioblastoma / genetics*
Glioblastoma / mortality
Glioblastoma / pathology
Humans
Immunoglobulin G / pharmacology
Neoplasm Recurrence, Local / classification
Neoplasm Recurrence, Local / genetics*
Neoplasm Recurrence, Local / mortality
Neoplasm Recurrence, Local / pathology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Primary Cell Culture
Prognosis
RNA, Messenger / genetics
RNA, Messenger / metabolism
Recombinant Fusion Proteins / pharmacology
Signal Transduction
Spheroids, Cellular / drug effects
Spheroids, Cellular / metabolism
Spheroids, Cellular / pathology
Survival Analysis
Temozolomide
fas Receptor / genetics*
fas Receptor / metabolism
fas Receptor / pharmacology

Substances

Antineoplastic Agents, Alkylating
Drug Combinations
FAS protein, human
Immunoglobulin G
RNA, Messenger
Recombinant Fusion Proteins
fas Receptor
Dacarbazine
Class Ia Phosphatidylinositol 3-Kinase
APG101
Temozolomide