Journal
SCIENCE
Volume 369, Issue 6501, Pages 276-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaz2193
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Funding
- National Cancer Institute (NCI) [P30 CA008748, R35 CA220508]
- NCI [1U2CCA233284]
- Pew Charitable Trusts [GC241069]
- Damon Runyon Cancer Research Foundation [GC240764]
- Pershing Square Sohn Cancer Research Alliance [GC239280]
- Baker Family Foundation
- American Brain Tumor Association [BRF1900019]
- Robert J. Kleberg Jr. and Helen C. Kleberg Foundation
- Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center
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The tumor microenvironment plays a critical regulatory role in cancer progression, especially in central nervous system metastases. Cancer cells within the cerebrospinal fluid (CSF)-filled leptomeninges face substantial microenvironmental challenges, including inflammation and sparse micronutrients. To investigate the mechanism by which cancer cells in these leptomeningeal metastases (LM) overcome these constraints, we subjected CSF from five patients with LM to single-cell RNA sequencing. We found that cancer cells, but not macrophages, within the CSF express the iron-binding protein lipocalin-2 (LCN2) and its receptor SCL22A17. These macrophages generate inflammatory cytokines that induce cancer cell LCN2 expression but do not generate LCN2 themselves. In mouse models of LM, cancer cell growth is supported by the LCN2/SLC22A17 system and is inhibited by iron chelation therapy. Thus, cancer cells appear to survive in the CSF by outcompeting macrophages for iron.
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