Brain metastases are linked to poor survival outcomes. For breast cancer cells to colonize the brain, they must undergo significant adaptive changes, suggesting that only a small proportion of cells present in primary tumours have this capability.
Our research, using preclinical models, lineage tracing, high-resolution imaging, and single cell sequencing, demonstrates that specific clones with brain tropism are enriched in certain genes, including those related to the neurogenesis pathway. The epithelial-to-neuronal transition, driven by transcription factors such as SOX4, allows these cells to thrive in the brain tumour microenvironment. However, this 'reprogramming' appears to occur in primary tumours rather than being a consequence of adaptive changes once the cells reach the brain. This suggests that a meticulous analysis of primary tumours may help predict this highly selective process. Additionally, studying clonal adaptation within the brain tumour microenvironment could help us identify other targets to disrupt the establishment of brain metastases, and improve patient outcomes.