Study summary · research use only
Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study used human brain tumor material, a humanized organotypic glioblastoma (GBM) model, and GBM mouse models to examine how myeloid cells interact with GBM cells to promote chemoresistance via GP130 receptor signalling. The authors report that nanomolar concentrations of the signaling peptide humanin promoted temozolomide (TMZ) resistance through DNA damage response (DDR) activation, and that mouse models with intratumoral humanin release showed accelerated blood-tumor barrier (BTB) formation. GP130 blockade reduced both DDR activity and BTB formation, which was associated with improved preclinical chemotherapeutic outcomes. The authors describe this as a mechanism for TMZ resistance and outline a strategy with predictive markers intended to improve chemotherapy for GBMs.
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.
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