Friction-induced budding of a cancer cell monolayer

The environment surrounding a tumor plays a crucial role in cancer cell dissemination. Within this microenvironment, cancer-associated fibroblasts (CAFs) can collectively combine their tensile stress to actively remodel tumors. Using circular clusters of cancer cell monolayers surrounded by CAFs, we generate structures that are reminiscent of multicellular buds observed for colorectal cancer. A supracellular contractile ring spontaneously assembles at the inner edge of the CAF monolayer and drives its closure on top of the cancer cells through a purse-string mechanism. This CAF-driven constriction triggers multilayering of cancer cells, culminating in the growth of a bud pinched by the CAF ring. We propose that this process is powered by frictional shear stress from CAF motion and develop a theoretical model based on continuum mechanics that quantitatively reproduces the experimental observations. The model captures the early reshaping of the cancer cell layer. Invoking a generic deformation threshold for multilayering, it identifies the physical conditions that favor budding and predicts how budding probability and size scale with initial cluster diameter. Our results establish a general framework for friction-induced morphogenesis in cell layers and reveal how active mechanical coupling between tumors and their microenvironment can shape tumor morphology and behavior.