Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype

Amanda Fitzpatrick, Marjan Iravani, Adam Mills, David Vicente, Thanussuyah Alaguthurai, Ioannis Roxanis, Nicholas C. Turner, Syed Haider, Andrew N. J. Tutt and Clare M. Isacke ()
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Amanda Fitzpatrick: The Institute of Cancer Research
Marjan Iravani: The Institute of Cancer Research
Adam Mills: The Institute of Cancer Research
David Vicente: The Institute of Cancer Research
Thanussuyah Alaguthurai: King’s College London
Ioannis Roxanis: The Institute of Cancer Research
Nicholas C. Turner: The Institute of Cancer Research
Syed Haider: The Institute of Cancer Research
Andrew N. J. Tutt: The Institute of Cancer Research
Clare M. Isacke: The Institute of Cancer Research

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Breast cancer leptomeningeal metastasis (BCLM), where tumour cells grow along the lining of the brain and spinal cord, is a devastating development for patients. Investigating this metastatic site is hampered by difficulty in accessing tumour material. Here, we utilise cerebrospinal fluid (CSF) cell-free DNA (cfDNA) and CSF disseminated tumour cells (DTCs) to explore the clonal evolution of BCLM and heterogeneity between leptomeningeal and extracranial metastatic sites. Somatic alterations with potential therapeutic actionability were detected in 81% (17/21) of BCLM cases, with 19% detectable in CSF cfDNA only. BCLM was enriched in genomic aberrations in adherens junction and cytoskeletal genes, revealing a lobular-like breast cancer phenotype. CSF DTCs were cultured in 3D to establish BCLM patient-derived organoids, and used for the successful generation of BCLM in vivo models. These data reveal that BCLM possess a unique genomic aberration profile and highlight potential cellular dependencies in this hard-to-treat form of metastatic disease.

Date: 2023
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DOI: 10.1038/s41467-023-43242-x

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