ABSTRACT During the development from epithelial neoplasms to invasive carcinoma, uncontrolled growth and proliferation in a confined space cause tumor cells survive in a prolonged overcrowding condition. However, the role of this aberrant physical stimulus induced by overcrowding in the invasiveness acquisition of epithelial cells remains unclear. Here, we first identified overcrowded cancer cells were more abundant at invasive foci in human cancer samples and mouse xenograft models. Combining with mechanical modelling, genetic manipulations and biophysical measurements, we revealed that prolonged overcrowding induces retentive invasiveness in cancer cells by triggering nanocorrugated topographic transition of plasma membrane. Further study demonstrated that the nanocorrugated topographic transition is induced by overcrowding-increased Laplace pressure and disrupts lipid raft-like domains organization to promote tumor invasion. Finally, suppressing nanocorrugated topographical transition of plasma membrane by strengthening membrane-cortex-attachment resists to tumor cell invasion in a mouse model of oncogenesis. This work reveals the profound effect of tissue-scale mechanical revolution-induced biophysical transition of cancer cells in driving tumor invasion.

Overcrowding Drives Tumor Invasion by Inducing Nanotopographical Transition of Plasma Membrane