EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3-dimensional cell migration

Microtubules have long been implicated to play an integral role inmetastatic disease, forwhich a critical step is the local invasion of tumor cells into the 3-dimensional (3D) collagen-rich stromalmatrix.Herewe showthat cellmigration of human cancer cells uses the dynamic formation of highly branched protrusions that are composed of amicrotubule core surroundedbycortical actin, a cytoskeletal organization that is absent incellson 2-dimensional (2D) substrates. Microtubule plus-end tracking protein End-binding 1 and motor protein dynein subunits light intermediate chain 2 and heavy chain 1, which do not regulate 2D migration, critically modulate 3D migration by affecting RhoA and thus regulate protrusion branching through differential assembly dynamics of microtubules. An important consequence of this observation is that the commonly used cancer drug paclitaxel is 100-fold more effective atblockingmigrationina 3Dmatrix than ona 2Dmatrix.Thisworkreveals the central role thatmicrotubule dynamics plays in powering cell migration in a more pathologically relevant setting and suggests further testing of therapeutics targetingmicrotubules tomitigatemigration.