Protrusion force and cell-cell adhesion play a critical role in collective tumor cluster migration.

While collective migration is shown to enhance invasive and metastatic potential in cancer, the mechanisms driving this behavior and regulating tumor migration plasticity remain poorly understood. This study provides a mechanistic framework explaining the emergence of different modes of collective migration under hypoxia-induced secretome. We focus on the interplay between cellular protrusion force and cell-cell adhesion using collectively migrating three-dimensional microtumors as models with well-defined microenvironment. Large microtumors show directional migration due to intrinsic hypoxia, while small microtumors exhibit radial migration in response to hypoxic secretome. Here, we developed the minimal multi-scale microtumor model (MSMM) to elucidate underlying mechanisms. We identified distinct migration modes within specific regions of protrusion force and cell-cell adhesion parameter space. We show that sufficient cellular protrusion force is crucial for both, radial and directional collective microtumor migration. Radial migration emerges when sufficient cellular protrusion force is generated, driving neighboring cells to move collectively in diverse directions. Within migrating tumors, strong cell-cell adhesion enhances the alignment of cell polarity, breaking the symmetric angular distribution of protrusion forces, and leading to directional microtumor migration. The integrated results from the experimental and computational models provide fundamental insights into collective migration in response to different microenvironment stimuli.