GPNMB Drives Brain Metastasis by Sculpting a Pathologic Endothelial-Immune Interactome.

Area of Science:

• Oncology
• Neuroscience
• Immunology

Background:

• Brain metastases (BM) represent a significant challenge with poor patient outcomes.
• The mechanisms by which circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and alter the brain microenvironment are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying CTCs' brain colonization.
• To identify novel therapeutic targets for treating brain metastases.

Main Methods:

• Spatially resolved multi-omic profiling of CTCs and BM.
• Experimental models and clinical data analysis.
• Investigated GPNMB's role in BBB disruption and immune modulation.

Main Results:

• Identified GPNMB, secreted by CTCs, as a key driver of vascular disruption and brain colonization.
• CBX3-induced GPNMB disrupts endothelial junctions via EGFR, CBL, FTO, and YTHDF2-dependent TJP1 methylation.
• GPNMB promotes immune infiltration and T cell exhaustion in the brain.
• Elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 correlate with BM progression.

Conclusions:

• GPNMB is a critical mediator of brain metastasis by remodeling the BBB and influencing the brain immune microenvironment.
• Dual blockade of GPNMB and PD1 demonstrates therapeutic potential against BM.
• GPNMB represents a promising target for precision immunotherapy in patients with brain metastases.