Contact percolation governs collective motility via mechano-chemical feedback in heterogeneous breast cancer.

Breast carcinomas are heterogeneous tissues containing cell populations with distinct molecular programs and mechanical states. How this heterogeneity drives collective invasion remains unclear. Tissue fluidization, the shift from a crowded, solid-like state to a more deformable and mobile one, promotes collective motion of cancer cells. Using percolation theory, which explains how connected clusters generate system-wide behavior, here we show that a critical fraction of motile cells expressing RAB5A, a membrane-trafficking regulator, triggers an abrupt transition to coordinated, flock-like movement in heterogeneous breast cancer monolayers. Above this threshold, RAB5A cells form connected networks that mechanically and chemically reprogram neighboring control cells. Under these conditions, control cells acquire aligned migratory protrusions, soften and elongate through E-cadherin-dependent EGFR-MAPK signaling. They further activate a STAT1/STAT2-dependent inflammatory gene program through both cell contact and soluble signals. Our findings reveal a mechano-chemical switch through which local tumor heterogeneity organizes tissue-wide fluidization, inflammation and invasive behavior in breast cancer.