Directional cell movement through tissues is controlled by exosome secretion

Abstract

Directional cell movement through tissues is critical for multiple biological processes and requires maintenance of polarity in the face of complex environmental cues. Here we use intravital imaging to demonstrate that secretion of exosomes from late endosomes is required for directionally persistent and efficient in vivo movement of cancer cells. Inhibiting exosome secretion or biogenesis leads to defective tumour cell migration associated with increased formation of unstable protrusions and excessive directional switching. In vitro rescue experiments with purified exosomes and matrix coating identify adhesion assembly as a critical exosome function that promotes efficient cell motility. Live-cell imaging reveals that exosome secretion directly precedes and promotes adhesion assembly. Fibronectin is found to be a critical motility-promoting cargo whose sorting into exosomes depends on binding to integrins. We propose that autocrine secretion of exosomes powerfully promotes directionally persistent and effective cell motility by reinforcing otherwise transient polarization states and promoting adhesion assembly.

Exosome secretion promotes chemotaxis of cancer cells

“…We then further purified UC-Exo by sedimentation into a density gradient of Optiprep (DG-Exo) as described previously. 6 Consistent with our previous publication, 6 Western blot analysis revealed that FN is carried by HT1080 UCExo as well as DG-Exo but not on MV ( Fig. 2A).…”

“…6 We further found that fibronectin carried by exosomes promotes cell adhesion, explaining the speed defect of exosome secretion-inhibited cells. 6 To explore the role of EVs and their cargoes in cancer cell chemotaxis, we performed a similar approach. Exosomes were isolated from the conditioned media of HT1080 fibrosarcoma cells by serial centrifugation (ultracentrifuged exosomes, UC-Exo).…”

“…20 In neutrophils, autocrine generation of bioactive lipids on exosomes enhances motility toward the chemoattractant N-formyL-MethionyL-LeucyL-Phenylalanine (fMLP). 21 In a previous report, 6 we showed that inhibition of exosome secretion by knockdown of Rab27a, Synaptotagmin7 or Hrs in cancer cells inhibits in vivo metastasis and motility of cancer cells in a chick embryo model system. In this model, exosome secretion controlled both cell speed and directionality; however the directional cues were unclear.…”

“…4 In cancer, exosomes have been shown to influence many tumor properties, including growth, angiogenesis, invasion, and metastasis. [6][7][8][9][10][11] Additional extracellular vesicles (EVs), known as microvesicles (MVs), are shed from the surface of cells and also have been implicated in numerous biologic phenotypes, including embryonic stem cell communication, oncogenic transformation, and inflammation. [12][13][14][15] A major function of exosomes appears to be promotion of cell motility.…”

“…[12][13][14][15] A major function of exosomes appears to be promotion of cell motility. 6,10,[16][17][18] Thus, exosomes have been shown to promote cell protrusion formation, 16 adhesion, 6,19 and cell polarity. 20 In neutrophils, autocrine generation of bioactive lipids on exosomes enhances motility toward the chemoattractant N-formyL-MethionyL-LeucyL-Phenylalanine (fMLP).…”