Extracellular vesicles released by non-small cell lung cancer cells drive invasion and permeability in non-tumorigenic lung epithelial cells

Andrea L Kasinski,Feng Tian,Anjali M Byappanahalli,Sean E Humphrey,Hana Kubo,Humna Hasan,Ikjot Singh Sohal,Sarah Copeland,Arthit Chairoungdua,Sarunya Kitdumrongthum,Zulaida Soto-Vargas

doi:10.1038/s41598-022-04940-6

Abstract

Extracellular vesicles (EVs) released from non-small cell lung cancer (NSCLC) cells are known to promote cancer progression. However, it remains unclear how EVs from various NSCLC cells differ in their secretion profile and their ability to promote phenotypic changes in non-tumorigenic cells. Here, we performed a comparative analysis of EV release from non-tumorigenic cells (HBEC/BEAS-2B) and several NSCLC cell lines (A549, H460, H358, SKMES, and Calu6) and evaluated the potential impact of NSCLC EVs, including EV-encapsulated RNA (EV-RNA), in driving invasion and epithelial barrier impairment in HBEC/BEAS-2B cells. Secretion analysis revealed that cancer cells vary in their secretion level, with some cell lines having relatively low secretion rates. Differential uptake of NSCLC EVs was also observed, with uptake of A549 and SKMES EVs being the highest. Phenotypically, EVs derived from Calu6 and H358 cells significantly enhanced invasion, disrupted an epithelial barrier, and increased barrier permeability through downregulation of E-cadherin and ZO-1. EV-RNA was a key contributing factor in mediating these phenotypes. More nuanced analysis suggests a potential correlation between the aggressiveness of NSCLC subtypes and the ability of their respective EVs to induce cancerous phenotypes.

Highlights

Extracellular vesicles (EVs) released from non-small cell lung cancer (NSCLC) cells are known to promote cancer progression
We show for the first time how extracellular vesicles (EVs) derived from these NSCLC cells differ in their ability to alter the homeostasis of non-tumorigenic epithelial cells, including promoting invasion of human bronchial epithelial cell line (HBEC) and BEAS-2B cells and impairing a non-tumorigenic epithelial barrier
EV secretion rate was evaluated in all cell lines based on the initial culture volume, as well as initial cell number, and fold change was calculated in comparison to HBEC cells

Summary

Introduction

Extracellular vesicles (EVs) released from non-small cell lung cancer (NSCLC) cells are known to promote cancer progression. Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and as modulators of the microenvironment that are important for maintaining homeostasis and for influencing disease pathogenesis, including cancer metastasis[15]. NSCLC EVs have been reported to be intimately involved in driving invasion31, migration[32], and metastasis[15], and inducing an epithelial-to-mesenchymal transition (EMT)[33,34,35] While these studies show how NSCLC-derived EVs promote cancer progression by evaluating distinct aspects of cancer, most of these studies use cancer cells as the targets with few exceptions

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Results

Conclusion