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

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. [Display omitted] •Interaction of myeloid and tumor (GBM) cells induces humanin expression•GBMs segregate inter-individually into humanin-sensitive or humanin-insensitive tumors•In sensitive GBMs, humanin induces cell-autonomous and systemic chemoresistance•Humanin-mediated therapy resistance can be addressed with clinically approved drugs Cheng et al. show that glioblastoma (GBM) and myeloid cell interaction initiates paracrine signaling via the peptide humanin. Humanin activates GP130 receptors on vascular and GBM cells resulting in blood-tumor barrier formation and DNA damage response (DDR). This represents a bifurcated resistance pathway for chemotherapy. Therapeutic efficacy is restored by GP130 blockade.