Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases
- PMID: 40016452
- PMCID: PMC12323702
- DOI: 10.1038/s41591-025-03530-z
Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases
Abstract
Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.
Conflict of interest statement
Competing interests: B.I. has received consulting fees and honoraria from Volastra Therapeutics Inc, Merck, AstraZeneca, Novartis, Eisai and Janssen Pharmaceuticals and has received research funding to Columbia University from Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, Merck, Regeneron and Synthekine. B.I. is a founder of Basima Therapeutics, Inc. C.G. has received consulting fees from Watershed Informatics. B.H. received consulting fees and honoraria from Amgen, Eisai and MJH Life Sciences. A.M.T. received research funding from Ono Pharmaceuticals. N.A.R. is currently an employee and shareholder of Synthekine Inc. B.S.H. has received consulting fees from AstraZeneca, Ideaya, Jazz Pharmaceuticals, Sorrento Therapeutics, Genentech-Roche, OncLive, Veeva, Athenium, Boxer, Dava Oncology and SAI-Med and research funding to Columbia University from Neximmune, Inc, Janssen and Genentech-Roche. A.D.A. is now an employee of Adaptimmune. J.B. is now an employee of Pfizer. S.W., .S.K.D, and G.S. are employees of Caris Life Sciences. A.S. received consulting fees and honoraria from Abbvie, Bristol Myers Squibb, Veracyte, Genentech, Medscape and Physician Education Resource, and research support from Boehringer Ingelheim. All remaining authors report no competing interests.
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