MECHANO-CHEMICAL FEEDBACK VIA CONTACT PERCOLATION REGULATES PHASE TRANSITION AND TRANSCRIPTIONAL STATE IN HETEROGENEOUS BREAST CANCER

Breast cancer (BC) progression is influenced by dynamic changes in tissue material properties via processes akin to solid-to-fluid phase transitions (PTs), that enable collective motility, immune activation, and tumor invasion. We recently demonstrated that RAB5A, an endocytic small GTPase, induces tissue fluidification, promotes BC progression, and triggers an inflammatory gene response via cGAS/STING pathway and the acquisition of malignant traits. While prior studies used genetically homogeneous models, BC exhibits mechanical and genetic heterogeneity, which role in PT and BC progression is poorly understood. Here, we reveal that contact percolation - the formation of interconnected cell networks - provides a robust framework to predict PTs in heterogeneous BC tissues. Using mixed populations of motile RAB5A-expressing and immotile control cells, combined with numerical modeling, we demonstrate that percolation of RAB5A clusters drives flocking-fluid collective motility and activates an inflammatory gene program in neighboring control cells. Simulations and experimental validation show that a phenotypic switch mechanism allows control cells to acquire motility characteristics as a function of RAB5A neighbors, a switch essential for full-scale flocking transition. This rewiring is linked to local density and collective motility, marked by lamellipodia formation and RAB5A-dependent actin remodeling in control cells. In both 2D and 3D models, contact-driven percolation triggers a pro-inflammatory transcriptional switch in non-RAB5A cells, mediated by secreted factors and direct physical interactions. Our findings establish contact percolation as a key mechanism for chemo-mechanical communication in mixed tumor populations, shedding light on tissue reorganization and immune modulation in BC invasion and metastasis.