Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes. What's new? In non-small cell lung cancer (NSCLC), chemoresistant phenotypes are enhanced among mesenchymal cells, while some other NSCLC cell subpopulations are inherently sensitive to chemotherapy. Whether the latter cells can receive a resistance phenotype via transfer from mesenchymal cells remains unclear. To identify a possible transfer mechanism, the authors of this study investigated small extracellular vesicles known as exosomes. In a human bronchial epithelial cell model, they show that mesenchymal NSCLC-derived exosomes from chemoresistant cells are capable of transferring resistance to chemosensitive epithelial cells. Recipient cells exhibited increased mRNA levels of the mesenchymal transcription factor ZEB1, suggesting a mechanism for chemoresistance induction.