Spatial ecology of breast cancer reveals co-evolution of proliferative and dormant niches.
BACKGROUND Cancer progression involves not only uncontrolled proliferation but also the strategic entry of tumour cells into reversible (quiescent) or irreversible (senescent) states of cell cycle arrest (G0). These states can give rise to rare persister-like cancer cells that survive hostile tumour microenvironment conditions, facilitating drug resistance, metastasis and disease relapse. Despite their importance, identifying and understanding the mechanisms regulating these cell populations remains challenging. METHODS We leveraged single-cell and spatially profiled primary breast tumours to quantify G0 arrest and proliferation decisions in cancer cells, revealing molecular and spatial features associated with proliferation-G0 dynamics. RESULTS We uncovered a G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity. Spatial analyses revealed distinct ecological niches: G0 cells inhabited protective niches with complement pathway activity proximal to CXCL10+ macrophages and myofibroblastic cancer-associated fibroblasts (CAFs), whereas proliferative zones were associated with CLEC9A+ dendritic cells and PERK signalling, with distinct drug sensitivities. CONCLUSIONS Our findings highlight key principles underpinning G0-proliferation dynamics and niche specialisation in breast cancer, offering novel insights into the spatial drivers of tumour heterogeneity and evolution.