Long-range mechanical force in colony branching and tumor invasion

The most concerned factors for cancer prognosis are tumor invasion and metastasis. The patterns of tumor invasion can be characterized as random infiltration to surrounding extracellular matrix (ECM) or formation of long-range path for collective migration. Recent studies indicate that mechanical force plays an important role in tumor infiltration and collective migration. However, how tumor colonies develop mechanical interactions with each other to initiate various invasion patterns is unclear. Using a micro-patterning technique, we partition cells into clusters to mimic tumor colonies and quantitatively induce colony-ECM interactions. We find that pre-malignant epithelial cells, in response to concentrations of type I collagen in ECM ([COL]), develop various branching patterns resembling those observed in tumor invasion. In contrast with conventional thought, these patterns require long-range (~ 600 μm) transmission of traction force, but not biochemical factors. At low [COL], cell colonies synergistically develop pairwise and directed branching mimicking the formation of long-range path. By contrast, at high [COL] or high colony density, cell colonies develop random branching and scattering patterns independent of each other. Our results suggest that tumor colonies might select different invasive patterns depending on their interactions with each other and with the ECM.