Before Tumor Arrival, the Brain is Already Compromised: 5-HIAA Remotely Reprograms Choroid Plexus Vasculature to Pave the Way for Leptomeningeal Metastasis

HUANG Yang^1,2,3, HOU Yifan^1,2,3, YANG Jiahui^1,2,3, CHI Yudan^1,2,3*

(¹Department of Radiology, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, China State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Shanghai 200040, China; ²Department of Neurosurgery, Huashan Hospital, Shanghai 200040, China; ³Institute for Translational Brain Research, Fudan University, Shanghai 200040, China)

Abstract:

The choroid plexus plays a crucial barrier role during LM (leptomeningeal metastasis), but the mechanisms by which cancer cells regulate the supportive premetastatic niche remain unclear. This study demonstrates that remodeling of the metabolic microenvironment alters the structure and function of choroid plexus blood vessels, thereby disrupting vascular integrity to promote metastatic colonization by tumors. The metabolite 5-HIAA (5-hydroxyindoleacetic acid) is aberrantly increased in the cerebrospinal fluid and choroid plexus. Before cancer cell invasion into the choroid plexus, extracellular vesicles containing 5-HIAA specifically target blood vessels, leading to vascular deformation, abnormal hemodynamics, impaired permeability, and enhanced cancer cell metastasis. Mechanistically, 5-HIAA remodels choroid plexus vessels by activating the aryl hydrocarbon receptor, characterized by aberrant expression of mechanoreceptors and tight junction proteins. Therefore, this study highlights the critical role of 5-HIAA in the formation of a supportive microenvironment and underscores metabolic factors that regulate choroid plexus plasticity, which may help prevent tumor metastatic colonization during the early stages of LM development.

CSTR: 32200.14.cjcb.2026.05.0001