Choroid plexus mast cells drive tumor-associated hydrocephalus

Area of Science:

• Neuroscience
• Immunology
• Oncology

Background:

• Tumor-associated hydrocephalus (TAH) is a frequent and fatal complication of brain metastases.
• The precise mechanisms driving TAH beyond mechanical obstruction remain unclear.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms underlying TAH.
• To identify potential therapeutic targets for TAH.

Main Methods:

• Single-nucleus RNA sequencing and spatial transcriptomics were employed to analyze cellular changes in the brain.
• Genetic fate tracing and knockout models were used to investigate the role of mast cells.
• In vitro studies utilized human pluripotent stem cell-derived choroid plexus organoids.

Main Results:

• A specific population of mast cells, choroid plexus mast cells (CPMCs), were identified and found to increase significantly during TAH.
• CPMCs were shown to disrupt choroid plexus epithelial cilia via the tryptase-PAR2-FoxJ1 pathway, leading to increased cerebrospinal fluid production.
• Tryptase levels in cerebrospinal fluid correlated with TAH clinical severity, and a tryptase inhibitor (BMS-262084) demonstrated efficacy in preclinical models.

Conclusions:

• Choroid plexus mast cells play a critical role in the pathogenesis of TAH by disrupting epithelial cilia and increasing cerebrospinal fluid production.
• Targeting mast cell tryptase presents a promising therapeutic strategy for managing TAH.