Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype.
Amanda FitzpatrickMarjan IravaniAdam MillsDavid VicenteThanussuyah AlaguthuraiIoannis RoxanisNicholas C TurnerSyed HaiderAndrew N J TuttClare M IsackePublished in: Nature communications (2023)
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.
Keyphrases
- cerebrospinal fluid
- copy number
- induced apoptosis
- small cell lung cancer
- squamous cell carcinoma
- spinal cord
- cell cycle arrest
- single cell
- genome wide
- end stage renal disease
- newly diagnosed
- endoplasmic reticulum stress
- gene expression
- spinal cord injury
- oxidative stress
- endothelial cells
- internal carotid artery
- signaling pathway
- risk assessment
- resting state
- cell death
- pi k akt
- brain metastases
- white matter
- human health
- blood brain barrier
- artificial intelligence
- climate change
- young adults
- functional connectivity
- cerebral ischemia