GPNMB Drives Brain Metastasis by Sculpting a Pathologic Endothelial–Immune Interactome
Menée à l'aide de lignées cellulaires, d'un modèle murin et d'échantillons de métastases cérébrales ayant pour origine un cancer du poumon, un cancer du sein ou un mélanome, cette étude met en évidence un mécanisme par lequel la surexpression de la protéine CBX3 par les cellules tumorales circulantes favorise le développement de métatastases cérébrales en induisant le remodelage de la barrière hémato-encéphalique via l'expression de la glycoprotéine transmembranaire GPNMB et une succession de réactions impliquant le récepteur EGFR et l'axe CXCL12–CXCR4
Brain metastasis remains a devastating disease with dismal prognosis. How circulating tumor cells (CTC) penetrate the blood–brain barrier (BBB) and reprogram the brain microenvironment remains unclear. Using spatially resolved multi-omics profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via the CXCL12–CXCR4 axis and induced time-course–dependent T-cell exhaustion within the brain microenvironment. Clinically, elevated CBX3+GPNMB+ CTCs and plasma CXCL12 were significantly associated with brain metastasis progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti–brain metastasis efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.
Cancer Discovery , résumé, 2026