Abstract
Multiple clones of cancer cells can seed metastases via collective invasion and dissemination. While it is known that cancer clones cooperate during invasion, the events leading to it and the effects it may have on metastasis are not known. In this study, we demonstrate that the 4T1 and 67NR breast cancer cell lines, which are clones isolated from the same metastatic tumor, sort from each other and go on to perform cooperative invasion. By time-lapse microscopy of heterogenous spheroids, we show that the invasive 4T1 cells migrate from the spheroid core to the spheroid edge and remain there, while the non-invasive 67NR cells move only within their initial compartment, resulting in cell sorting. Following cell sorting, 4T1 cells lead the 67NR cells in cooperative invasion strands. Knockdown of the invadopodia protein Tks5 in 4T1 cells demonstrates that invasion requires invadopodia only in leader cells, and not in follower cells. Importantly, in the lung clonogenic assay, we demonstrate that cells without invadopodia can engage in cooperative metastasis. Altogether, our results suggest that a few cells with invadopodia could be sufficient to drive the metastasis of cell clusters from heterogeneous tumors.
Competing Interest Statement
The authors have declared no competing interest.
