Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype.
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Authors
Fitzpatrick, A
Iravani, M
Mills, A
Vicente, D
Alaguthurai, T
Roxanis, I
Turner, NC
Haider, S
Tutt, ANJ
Isacke, CM
Iravani, M
Mills, A
Vicente, D
Alaguthurai, T
Roxanis, I
Turner, NC
Haider, S
Tutt, ANJ
Isacke, CM
Document Type
Journal Article
Date
2023-11-16
Date Accepted
2023-11-03
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.
Citation
Nature Communications, 2023, 14 (1), pp. 7408 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Molecular Cell Biology
Molecular Oncology
Directorate Breast Canc
Molecular Oncology
Directorate Breast Canc