Less local mechanical resistance of the ECM can drive bursts in LCC or HCC. a) Holes were introduced into HCC at 0 h, into which cells burst out from the aggregate when followed over 12 h. Shown is the maximum intensity projection (scale bar = 100 µm). Zoomed insets show the cells bursting in the direction of the three holes (scale bar = 50 µm). b) Percentage of bursts in HCC with (+) and without (‐) holes introduced. N = 12 each. c) Simulation results for the time evolution of a cancer aggregate. The initial distribution of cancer cells and collagen was chosen analogous to the experimental data (scale bar = 100 µm). d) Sketch representing series of events over 0–8 h triggering coordinated pressure‐driven burst‐like dispersal of cells. [0 h] Cells at the periphery of oblate aggregates attach to the LCC via integrins (see legend and zoomed inset). Internal pressure remains low. [4 h] The ECM attachment sculpts a shape change. Pressure starts to be disturbed. [4–8 h] Volume of cells increases within aggregates, raising the internal pressure. From [8 h] onward, aggregates are unable to sustain the pressure increase and expel cells collectively in the directions of least mechanical resistance (green gradient (legend) depicts collagen density (in‐homogeneity in LCC)). e) Sketch of signaling events that precede the bursts. In the initial hours, once cells attach to the collagen fibers, the cell–ECM adhesions trigger the phosphorylation, and thus, activation of the myosin light chain. This leads to the binding of myosin II to actin cables, initiating the acto‐myosin‐based contraction of cells. The succeeding events depend on the rigidity of the ECM. In the presence of a stiff ECM (HCC), the cells receive the necessary mechanical feedback from stable cell– ECM adhesions that sustain a force balance and promote cell survival. Conversely, when the cells are surrounded by soft ECM (LCC), poor mechanotransduction stems from unstable cell–ECM adhesions, as the cells contract while pulling on the ECM. Such a failed force balance leads to drastic consequences such as cell swelling, possibly due to anoikis, that ultimately causes cell death. As a result, in the stiff ECM scenario, the aggregates grow beyond 8 h unperturbed, and within the same time span in the soft ECM case, the aggregates burst into the regions that provide the least mechanical resistance, thereby releasing the pressure (refer to (d)) in the aggregates.