ABSTRACT
Collective cell migration during morphogenesis, cancer metastasis, and wound healing depends on the emergence of leader cells at the migration front. However, the cellular changes that enable only a few cells to become the leader cells, remain elusive. Here we show that the leader cells in Drosophila embryo and mammalian epithelial monolayer emerge through a mechanosensitive relocalization of lysosomes. Before the leader cells display their characteristic lamellipodial protrusions, lysosomes accumulate at their leading periphery. Promoting this lysosome accumulation augments the leader cell emergence, while inhibiting it suppresses the latter. Moreover, experiments modulating cellular forces by chemical inhibition, optogenetics, and micropatterning show that peripheral accumulation of lysosomes depends on the actomyosin contractility. Mechanistically, peripheral lysosomes associate with the inactive form of small RhoGTPase Rac1 and remove it from the vicinity of plasma membrane. Removal of inactive Rac1 molecules leads to an increased Rac1-activity at the leading periphery, triggering actin polymerization and lamellipodium formation. Taken together, lysosome appears as a unique intracellular platform that links mechanical and biochemical signals and thereby controls the emergence of leader cells. We, therefore, discover a previously unknown function of lysosome in collective cell migration, significantly expanding its scope in cell and developmental biology.
SIGNIFICANCE STATEMENT Leader cells have profound effects on the efficacy of wound healing, morphogenesis, and cancer metastasis. Yet, it remains intriguing how these special cells, with their remarkable lamellipodial protrusions, emerge from a seemingly homogeneous population. Here, using an interdisciplinary approach, which combines live-cell microscopy, optogenetic manipulation, and micropatterning, we discover that a cellular organelle, lysosome, changes its position in response to the cellular force-field and accumulates at the leading periphery of the emerging leader cells. In these cells, peripheral lysosome accumulation induces polymerization of actin cytoskeleton and formation of lamellipodial protrusions. Together, our results reveal a critical and unique role of lysosomes in collective cell migration, beyond the conventional reputation of this organelle as a cellular compartment dedicated for catabolism.
Competing Interest Statement
The authors have declared no competing interest.
