Invadopodia enable cooperative invasion and metastasis of breast cancer cells

Invasive and non-invasive cancer cells can invade together during cooperative invasion. However, the events leading to it, role of the epithelial-mesenchymal transition and the consequences this may have on metastasis are unknown. In this study, we demonstrate that the isogenic 4T1 and 67NR breast cancer cells sort from each other in 3D spheroids, followed by cooperative invasion. By time-lapse microscopy, we show that the invasive 4T1 cells move more persistently compared to non-invasive 67NR, sorting and accumulating at the spheroid-matrix interface, a process dependent on cell-matrix adhesions and independent from E-cadherin cell-cell adhesions. Elimination of invadopodia in 4T1 cells blocks invasion, demonstrating that invadopodia requirement is limited to leader cells. Importantly, we demonstrate that cells with and without invadopodia can also engage in cooperative metastasis in preclinical mouse models. Altogether, our results suggest that a small number of cells with invadopodia can drive the metastasis of heterogeneous cell clusters. Cooperative invasion requires the formation of invadopodia in the leader cells, and a small number of leader cells may be enough to facilitate cooperative invasion and metastasis, including non-invadopodia forming cancer cells.

Automated summary

Invasive and non-invasive cancer cells can invade together during cooperative invasion. A small number of invasive cells with invadopodia can drive the metastasis of heterogeneous cell clusters, and the formation of invadopodia in leader cells is essential for cooperative invasion.