Exosome Secretion Is Enhanced by Invadopodia and Drives Invasive Behavior

TLDR

Exosome secretion from multivesicular endosomes is upregulated in cancer and promotes aggressive behavior, yet its regulatory control remains poorly understood. In cancer cells, invadopodia serve as specific docking and secretion sites for CD63‑ and Rab27a‑positive MVEs, linking actin‑based structures to exosome release. Blocking invadopodia formation markedly reduces exosome secretion, while exosomes in turn modulate invadopodia formation, stabilization, and protease exocytosis, thereby enhancing cellular invasion and revealing a synergistic interaction that drives cancer cell invasiveness.

Abstract

Unconventional secretion of exosome vesicles from multivesicular endosomes (MVEs) occurs across a broad set of systems and is reported to be upregulated in cancer, where it promotes aggressive behavior. However, regulatory control of exosome secretion is poorly understood. Using cancer cells, we identified specialized invasive actin structures called invadopodia as specific and critical docking and secretion sites for CD63- and Rab27a-positive MVEs. Thus, inhibition of invadopodia formation greatly reduced exosome secretion into conditioned media. Functionally, addition of purified exosomes or inhibition of exosome biogenesis or secretion greatly affected multiple invadopodia life cycle steps, including invadopodia formation, stabilization, and exocytosis of proteinases, indicating a key role for exosome cargoes in promoting invasive activity and providing in situ signaling feedback. Exosome secretion also controlled cellular invasion through three-dimensional matrix. These data identify a synergistic interaction between invadopodia biogenesis and exosome secretion and reveal a fundamental role for exosomes in promoting cancer cell invasiveness.