Cancer Cells Survive Iron-Poor Cerebrospinal Fluid Using Lipocalin-2

The existence of leptomeningeal metastases poses a conundrum because the cerebrospinal fluid (CSF) is suboptimal for growth, possessing low levels of essential micronutrients such as iron. Using single-cell RNA sequencing of cells from the CSF of five patients with leptomeningeal metastases arising from breast or non–small cell lung cancer, Chi and colleagues found that cancer cells—but not the immune cells that were also present in the CSF—highly expressed the gene encoding the secreted ferric iron–binding protein lipocalin-2 (LCN2; also known as NGAL) and the gene encoding the LCN2 receptor SLC22A17. Enzyme-linked immunosorbent assays and flow cytometry analyses confirmed elevated protein expression of LCN2 and SLC22A17 by the cancer cells. In experiments with a mouse model of leptomeningeal metastasis in which leptomeningeal metastases also exhibited increased expression of LCN2 protein and the corresponding mRNA along with SLC22A17 protein and the associated mRNA, knockdown of LCN2 levels in the cancer cells inhibited tumor growth and enhanced survival when the cancer cells resided in the leptomeninges but not in iron-replete sites. Additionally, overexpression of LCN2 enabled cancer cells that otherwise had no propensity to grow in the leptomeninges to do so and reduced the duration of survival. Mechanistically, inflammatory cytokines (including IL6, IL8, and IL1β) produced by CSF-derived macrophages triggered LCN2 expression in experiments using mouse models and in coculture experiments using patient samples. Additionally, hypoxia and iron metabolism are tightly connected and the CSF is generally hypoxic; indeed, mouse experiments established that leptomeningeal tumors were hypoxic, and in vitro experiments showed that knockdown of LCN2 levels inhibited leptomeningeal cancer cells' ability to survive under hypoxic conditions, whereas overexpression of LCN2 enhanced these cells' ability to withstand hypoxia. Finally, further investigation demonstrated that LCN2 enabled leptomeningeal metastases to scavenge iron from the environment, outcompeting macrophages for this essential micronutrient. In summary, this work shows how cancer cells can overcome one of the major barriers to metastasis to the leptomeninges, providing insight into this typically fatal condition.

Chi Y, Remsik J, Kiseliovas V, Derderian C, Sener U, Alghader M, et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 2020;369:276–82.

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