Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis.
Open accessAbstract
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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scRNAseq analysis done on tumor cells isolated from the leptomeninges of patients with metastatic growth showed high expression of the iron-binding protein lipocalin-2 (Lcn2) and its receptor SLC22A17, and Lcn2 expression, which is induced by macrophage cytokine release, allows tumor cells to grow more effectively in the low nutrient CSF environment.
“scRNAseq analysis done on tumor cells isolated from the leptomeninges of patients with metastatic growth showed high expression of the iron-binding protein lipocalin-2 (Lcn2) its receptor SLC22A17”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Chi et al., 2020
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- Authors
- Chi, Y., Remsik, J., Kiseliovas, V., Derderian, C., Sener, U., Alghader, M., Saadeh, F., Nikishina, K., Bale, T., Iacobuzio-Donahue, C., Thomas, T., Pe’er, D., Mazutis, L., & Boire, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
- Columbia University (US)
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
- Corresponding author
- Boire, Adrienne
- ORCID
- Venue
- Science
- Published
- 2020-07-17
- Volume
- 369
- Issue
- 6501
- Pages
- 276-282
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7816199
- OpenAlex
- W3043398874
- Cited by
- 320
- References
- 47
- Citations by year
- 2026: 46 · 2025: 69 · 2024: 69 · 2023: 56 · 2022: 37 · 2021: 34 · 2020: 9
- FWCI
- 19.12
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R35 CA220508, 1U2CCA233284, P30 CA008748)
- Pew Charitable Trusts (GC241069)
- Damon Runyon Cancer Research Foundation (GC240764)
- American Brain Tumor Association (BRF1900019)
- Pershing Square Sohn Cancer Research Alliance (GC239280)
- The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (n/a)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- leptomeningeal metastasis, neutrophil gelatinase-associated lipocalin, SLC22A17, iron acquisition, tumor microenvironment, cerebrospinal fluid, cancer-associated macrophages, iron chelation therapy, central nervous system metastasis, single-cell RNA sequencing
- MeSH terms
- Lipocalin-2, Animals, Humans, Iron, Macrophages, Meningeal Neoplasms, Mice, Tumor Microenvironment
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