Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity

Odessa Schillaci,Francesca Monteleone,Maria Antonietta Di Bella,Dolores Di Vizio,Simona Fontana,Simona Taverna,Riccardo Alessandro

doi:10.1038/s41598-017-05002-y

Abstract

The goal of this study was to understand if exosomes derived from high-metastatic cells may influence the behavior of less aggressive cancer cells and the properties of the endothelium. We found that metastatic colon cancer cells are able to transfer their amoeboid phenotype to isogenic primary cancer cells through exosomes, and that this morphological transition is associated with the acquisition of a more aggressive behavior. Moreover, exosomes from the metastatic line (SW620Exos) exhibited higher ability to cause endothelial hyperpermeability than exosomes from the non metastatic line (SW480Exos). SWATH-based quantitative proteomic analysis highlighted that SW620Exos are significantly enriched in cytoskeletal-associated proteins including proteins activating the RhoA/ROCK pathway, known to induce amoeboid properties and destabilization of endothelial junctions. In particular, thrombin was identified as a key mediator of the effects induced by SW620Exos in target cells, in which we also found a significant increase of RhoA activity. Overall, our results demonstrate that in a heterogeneous context exosomes released by aggressive sub-clones can contribute to accelerate tumor progression by spreading malignant properties that affect both the tumor cell plasticity and the endothelial cell behavior.

Highlights

Human tumors display a significant intratumor heterogeneity that influences their metastatic potential and therapeutic resistance
We demonstrate that exosomes derived from cells with high metastatic potential can modulate phenotypic plasticity in less aggressive cancer cells and elicit structural alterations of endothelial cells in a RhoA/ROCK dependent fashion
We found that SW620Exos significantly increased, both migration (Fig. 3A) and invasion (Fig. 3B) of non-metastatic cells in a dose-dependent manner. These results indicate that metastatic cells can transfer their round/amoeboid phenotype to non-amoeboid cancer cells via exosomes and that this morphological transition is associated with the acquisition of a more aggressive behavior

Summary

Introduction

Human tumors display a significant intratumor heterogeneity that influences their metastatic potential and therapeutic resistance. A growing number of studies suggest that the tumor microenvironment (TME), which contributes to a functional crosstalk between different cell types, plays an important role in determining the heterogeneity observed within and across tumors[4]. Exosomes are nanometer-sized vesicles (40–100 nm diameter) of endocytic origin that are released by different cell types under both normal and pathological conditions They function as cell free messengers that could potentially affect tumor heterogeneity[15], due to the nature of the molecules (proteins, mRNAs, miRNAs and lipids) that they transport. We demonstrate that exosomes derived from cells with high metastatic potential can modulate phenotypic plasticity in less aggressive cancer cells and elicit structural alterations of endothelial cells in a RhoA/ROCK dependent fashion This contributes to create a permissive microenvironment for tumor dissemination

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