Year: 2025
Type: conference-abstract
Abstract: Leptomeningeal metastasis (LM) is a fatal complication of cancer characterized by the spread of cancer cells within the cerebrospinal fluid (CSF)-filled spaces. Despite aggressive treatment, neurologic deficits accumulate rapidly, and patients generally succumb to LM within months. Previous work from our lab and others demonstrates that hematogenously disseminated cancer cells reach the leptomeninges through the choroid plexus (ChP), highly vascularized structures within the ventricles that generate CSF. As specialized secretory tissues, ChP are master regulators of CSF composition, and orchestrators of leptomeningeal homeostasis. Their unique structure and brisk perfusion also allow ChP to play a neurosurveillance role in the CNS. We hypothesize that ChP alterations occur prior to the arrival of cancer cells into the leptomeninges, anticipating cancer cell arrival, and generating potential early, actionable biomarkers of LM. Interrogating the transcriptome of human and mouse samples at the single cell level, we captured the ChP response to tumors outside the CNS. Before LM, when patients and mice harbor only non-CNS tumors, the ChP transcriptome displays increased vascular permeability and ECM remodeling signatures. This condition evolves with disease progression. In metastatic ChP, we observe sustained, robust inflammation characterized by influx of immune cells, and corresponding cytokine storm. Consistent with the ChP being a pre-metastatic niche, macrophages precede cancer cells in the ChP, leading to increased proteolytic activity, ECM remodeling and ChP permeability. Interestingly, CSF from patients harboring LM is enriched in collagen1 fragments, MMP2, MMP9 and TIMP1, showing that ChP alterations are carried into the CSF. Pharmacological and genetic inhibition of each of the described factors in vivo, results in decreased LM burden. We show that ChP act as orchestrators of a pre-metastatic niche. The cooperation between cancer and ChP cells creates a “wound that never heals” state that fuels LM, suggesting novel therapeutic approaches to prevent development of LM.
Source: Neuro-Oncology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416139749
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