Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.

Autor:	Cheng J; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany; Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China., Li M; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Motta E; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch, Germany., Barci D; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Song W; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Zhou D; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Li G; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Zhu S; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Yang A; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany., Vaillant BD; Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Imhof A; Protein Analysis Unit, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, Martinsried, Germany., Forné I; Protein Analysis Unit, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, Martinsried, Germany., Spiegl-Kreinecker S; Department of Neurosurgery, Medical Faculty, Johannes Kepler University Linz, Linz, Austria; Clinical Research Institute for Neurosciences, Johannes Kepler University Linz, Linz, Austria., Zhang N; Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China., Katayama H; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bhat KPL; Department of Cancer Biology, Mayo Clinic, Scottsdale, AZ, USA., Flüh C; Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany., Kälin RE; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany; Department of Neurosurgery, Medical Faculty, Johannes Kepler University Linz, Linz, Austria., Glass R; Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Munich, Munich, Germany; Institute of Surgical Research at the Walter Brendel Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany. Electronic address: rainer.glass@med.uni-muenchen.de.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Aug 20; Vol. 5 (8), pp. 101658. Date of Electronic Publication: 2024 Jul 24.
DOI:	10.1016/j.xcrm.2024.101658
Abstrakt:	The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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