In order to survive within the remote and harsh anatomical microenvironments of the central nervous system, the disseminated cancer cells that cause rare yet deadly leptomeningeal metastases (LM) hijack crucial iron micronutrients from native macrophages, researchers report. The work highlights the remarkable plasticity of tumor cells and reveals potential new avenues for treating these particularly intractable advanced cancer complications. On rare occasions, cancer cells infiltrate the relatively isolated spaces of the central nervous system filled with cerebrospinal fluid (CSF) and metastasize to the leptomeningeal membranes that line the brain and spinal cord. Nutrient-and oxygen-deprived, and loaded with patrolling immune cells, the CSF presents a hostile environment to outsiders – yet somehow, cancer cells survive and thrive in this challenging environment. To investigate how cancer cells overcome these constraints, Yudan Chi and colleagues used single-cell RNA sequencing to study CSF samples from five patients with LM. The authors found that these cells utilize a high-affinity iron collection system. In CSF, iron is a limited but highly sought resource crucial to cell metabolism and DNA synthesis. Cancer cells that express an iron-capturing gene collect iron more efficiently, outcompeting healthy CSF macrophages for the crucial resource. Thus, the mechanism allows LM cells to survive in nutrient-deprived environments while potentially escaping immune attack by limiting the supply of vital iron to macrophages. “Few studies have focused on the biochemical composition of the CSF in the setting of leptomeningeal metastasis, and the study of Chi et al. contributes to bridging this knowledge gap,” writes Livia Garzia and Michael Taylor in a related Perspective.
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