Leptomeningeal metastatic cancer cells induce a permissive choroid plexus vasculature through extracellular-vesicle-derived 5-HIAA signaling.

The choroid plexus acts as a crucial barrier in leptomeningeal metastasis (LM), yet the mechanisms through which cancer cells modulate supportive premetastasis niches remain unclear. Here, we show that remodeling of the metabolic microenvironment modifies the structure and function of choroid plexus vessels, which destroy vascular integrity to facilitate metastatic colonization. An abnormal increase in the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid and choroid plexus indicates a predisposition. Before initially invading the choroid plexus through cancer cells, 5-HIAA-containing extracellular vesicles specifically target vessels, resulting in vascular distortion, abnormal hemodynamics, compromised permeability and facilitation of cancer cell traversal. Mechanistically, aryl hydrocarbon receptor pathway activation by 5-HIAA is linked to choroid plexus vascular remodeling, characterized by aberrant expression of mechanoreceptors and tight junction proteins. Hence, our findings underscore the key role of 5-HIAA in supportive niche formation and highlight metabolic determinants that govern choroidal plasticity to effectively prevent metastatic colonization in LM initiation.