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

Author

Listed:
  • Amanda Fitzpatrick

    (The Institute of Cancer Research
    King’s College London)

  • 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
    The Royal Marsden NHS Foundation Trust)

  • Syed Haider

    (The Institute of Cancer Research)

  • Andrew N. J. Tutt

    (The Institute of Cancer Research
    King’s College London
    Guy’s and St Thomas’ NHS Foundation Trust)

  • Clare M. Isacke

    (The Institute of Cancer Research)

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.

Suggested Citation

  • Amanda Fitzpatrick & Marjan Iravani & Adam Mills & David Vicente & Thanussuyah Alaguthurai & Ioannis Roxanis & Nicholas C. Turner & Syed Haider & Andrew N. J. Tutt & Clare M. Isacke, 2023. "Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43242-x
    DOI: 10.1038/s41467-023-43242-x
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