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

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

  • Cell Rep Med. 2024 Aug 20;5(8):101658. doi: 10.1016/j.xcrm.2024.101658.
Jiying Cheng 1,  Min Li 2,  Edyta Motta 3,  Deivi Barci 2,  Wangyang Song 2,  Ding Zhou 2,  Gen Li 2,  Sihan Zhu 2,  Anru Yang 2,  Brian D Vaillant 4,  Axel Imhof 5,  Ignasi Forné 5,  Sabine Spiegl-Kreinecker 6,  Nu Zhang 7,  Hiroshi Katayama 8,  Krishna P L Bhat 9,  Charlotte Flüh 10,  Roland E Kälin 11,  Rainer Glass 12
Affiliations

Affiliations

  • 1 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.
  • 2 Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany.
  • 3 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch, Germany.
  • 4 Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
  • 5 Protein Analysis Unit, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, Martinsried, Germany.
  • 6 Department of Neurosurgery, Medical Faculty, Johannes Kepler University Linz, Linz, Austria; Clinical Research Institute for Neurosciences, Johannes Kepler University Linz, Linz, Austria.
  • 7 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.
  • 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9 Department of Cancer Biology, Mayo Clinic, Scottsdale, AZ, USA.
  • 10 Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.
  • 11 Neurosurgical Research, University Hospital, LMU Munich, Munich, Germany; Department of Neurosurgery, Medical Faculty, Johannes Kepler University Linz, Linz, Austria.
  • 12 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.
PMID: 39053460 DOI: 10.1016/j.xcrm.2024.101658
Abstract

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.

Keywords

DDR; DNA damage response; GP130; IL6ST; TAM; blood-tumor barrier; chemotherapy; glioblastoma; humanin; temozolomide; tumor-associated myeloid cells.

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