Contact percolation sets flocking phase transition via chemo-mechanical feedback in heterogeneous breast cancer

Breast cancer progression is driven by dynamic changes in tissue mechanics that promote phase transitions toward collective cell movement, immune activation, and invasion. While previous investigations primarily employed model systems of genetically identical cells, breast carcinoma consists of heterogeneous cell populations varying in genetic and mechanical traits. The complex interplay between this diversity and collective cell dynamics, affecting phase transitions and tumor progression, remains largely unexplored. Here, we interpreted our experimental data through contact percolation theory to uncover a chemo-mechanical switch underlying a phase transition via the emergence of flocking motility in heterogeneous breast cancer tissues. Using engineered mixtures of motile RAB5A-expressing cells and immotile controls, we demonstrate that interconnected system-spanning clusters of fluidized RAB5A cells induce a phenotypic switch in neighboring cells, enabling them to acquire full-scale, flocking-like motility and reprogram their transcriptional state. This transition is accompanied by the activation of pro-inflammatory gene programs. Our theoretical modelling supports a mechanism by which local cell composition drives a motility switch critical for the emergence of coordinated, system-wide movement. These findings highlight the role of mechanical heterogeneity in tumor progression and identify contact percolation as a fundamental mechanism driving dynamic tissue re-organization and immune modulation at the root of breast cancer invasion and metastasis.