CXCL1-CXCR2 signaling mediates cancer cell growth and response to radiation therapy in leptomeningeal metastasis.

Authors

Ahmed M Osman, Francis Y He, Jan Remsik, Jenna Snyder, Seogho Son, Sophia Toomey, Rachel Estrera, Neil Ari Wijetunga, Branavan Manoranjan, Ana Rita Nobre, Morgan Freret, David Guber, Kiana Chabot, Sofia Piedrafita-Ortiz, Xinran Tong, Helen Wang, Min J Li, Marisa Rose, Andrew J Dunbar, Ross L Levine, Jonathan T Yang, Adrienne Boire

Published in

Science translational medicine. Volume 18. Issue 868. Pages eaeh7968. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer. Proton craniospinal irradiation (pCSI) has emerged as a promising life-prolonging intervention for patients with LM, but response to this treatment varies. Here, we aimed to characterize the molecular basis of pCSI resistance and response. Proteomic analysis of cerebrospinal fluid (CSF) collected from patients with LM at baseline (before pCSI), and at multiple time points posttreatment, identified the chemokine C-X-C-motif ligand 1, CXCL1, associated with LM growth. Higher CXCL1 levels in the CSF before pCSI correlated with worse response to this treatment. To define the role of CXCL1 in LM, we established syngeneic mouse models of LM-CSI. We found that both metastatic cancer and host cells generate CXCL1. Genetic interruption of Cxcl1 expression in metastatic cancer, but not host cells, impaired cancer cell growth within the leptomeninges. Moreover, we found that Cxcr2, the primary receptor for Cxcl1, was widely expressed within the LM microenvironment. A subset of LM cancer cells expressed Cxcr2, and this population was enriched over time in the leptomeninges. Transcriptomic profiling of this rare population revealed enrichment in pathways associated with cell cycle progression. In patients, we found that higher expression of CXCR2 before pCSI correlated with worse overall survival. Last, in preclinical models, interruption of Cxcl1-Cxcr2 signaling with intrathecally delivered Cxcr2 antagonist hampered LM growth and sensitized cancer cells to CSI. Our results demonstrate that the Cxcl1-Cxcr2 signaling axis mediates LM growth and identifies a potential actionable intervention to improve response to pCSI and halt LM progression.

PMID:
42777082
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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