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

Abstract

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.Lung cancer is the leading cause of cancer mortality worldwide, 1 largely due to metastasis and development of treatment resistance. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and most patients present with late stage disease and poor survival prospects. 1The developmental epithelial-to-mesenchymal transition (EMT) process is the phenotypic depolarisation of epithelial cells to elongated mesenchymal cells, due to downregulation of epithelial properties and remodelling of the cytoskeleton to enhance migratory potential. 2 EMT has been associated with metastasis and acquired resistance to cancer therapies 3,4 in various cancers, including NSCLC. 5 EMT is the phenotypic depolarisation of epithelial cells to elongated mesenchymal cells, due to downregulation of epithelial properties and remodelling of the cytoskeleton to enhance migratory potential. 2 The loss of epithelial characteristics is associated with E-cadherin loss and gain of mesenchymal markers, such as vimentin.2 E-cadherin is primarily regulated by canonical EMT transcription factors (Snail, Slug, Twist and Zeb1/2), that repress E-cadherin through interactions with the proximal region of the E-cadherin promoter. Recently, it has been demonstrated that EMT is expendable for metastasis but is an essential step in the development of chemoresistance in breast ...

Exosomes play roles in sequential processes of tumor metastasis

“…Similar results were discovered in hepatocellular carcinoma (HCC) in which oncogenic RNAs and proteins, like S100 family members and caveolins could be horizontal transferred to neighboring and distant hepatocytes through exosomes, enhancing the migratory and invasive abilities . In lung cancer, exosomes derived from mesenchymal, oncogenically transformed lung cells could transfer mesenchymal phenotypes and even chemoresistance to recipient cells, via the exosomal transfer of a master epithelial‐mesenchymal transition (EMT) transcription factor, ZEB1 mRNA …”

Breast Cancer‐Derived Exosomes Reflect the Cell‐of‐Origin Phenotype

“…This transition from an epithelial to mesenchymal stage, termed epithelial‐to‐mesenchymal transition (EMT), has profound impacts on all stages of cancer progression from initiation, growth, and metastasis, to resistance to therapy . Generally, mesenchymal‐like cancer cells are reported to be migratory, less sensitive to chemotherapies, and show low proliferative ability . The characteristics of these mesenchymal‐like cancer cells are thought to be a common cause for metastatic spread .…”

“…Consequently, a loss of E‐cadherin expression can increase breast cancer cell motility and invasiveness. We recently demonstrated that exosomes released by mesenchymal lung cancer cells can confer chemoresistance and mesenchymal traits to recipient epithelial lung cancer cells . However, just how closely the protein content of breast cancer‐derived exosomes reflects the epithelial and mesenchymal state of parent cancer cells remains inconclusive.…”

The cancer exosomes: Clinical implications, applications and challenges

“…revealed that nonsmall cell carcinoma cell‐derived exosome contained anaplastic lymphoma kinase (ALK) carrier reduced the therapeutic effect of ALK inhibitors. Lobb et al . demonstrated that mesenchymal nonsmall cell lung cancer (NSCLC) cells changed the chemotherapy tolerance of recipient cells with increased expressed exosomal ZEB1 mRNA (Table ).…”