Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer

The principal cause of death in cancer patients is metastasis, which remains an unresolved problem. Conventionally, metastatic dissemination is linked to actomyosin-driven cell locomotion. However, the locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, a complementary mechanism of metastatic locomotion powered by dynein-generated forces is identified. These forces arise within a non-stretchable microtubule network and drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. It is also shown that the dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network formed by spatially confining granular hydrogel scaffolds (GHS) made up of microscale hydrogel particles (microgels). These results indicate that the complementary motricity mediated by dynein is always necessary and, in certain instances, sufficient for disseminating metastatic breast cancer cells. These findings advance the fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis. Breast cancer cells utilize a complementary metastatic locomotion mechanism in the absence of actomyosin contractility via dynein-driven sliding of the microtubules in respect to the F-actin cytoskeleton and cell-collagen adhesions in the adhesion-guided 'dendritic'-like protrusions. Either actomyosin- or dynein-driven cell motility is sufficient for carcinoma cell migration along the artificial anisotropic collagen 'fibers', indicating mutually compensating, dynamically balanced metastasis mechanism.image