Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.
Cell Rep Med
; 5(8): 101658, 2024 Aug 20.
Article
in En
| MEDLINE
| ID: mdl-39053460
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
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Signal Transduction
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Drug Resistance, Neoplasm
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Myeloid Cells
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Cytokine Receptor gp130
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Temozolomide
Limits:
Animals
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Humans
Language:
En
Journal:
Cell Rep Med
Year:
2024
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
/
EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA