Hepatocyte Growth Factor and β1-integrin signalling axis drives tunneling nanotube formation in A549 lung adenocarcinoma cells

Abstract

AbstractTunneling nanotubes (TNTs) are thin cytoplasmic protrusions involved in long-distance cellular communication. The presence of TNTs has been foundin vivoandin vitrostudies in non-small cell lung cancer (NSCLC). Cancer cells transport a range of organelles and signalling molecules along TNTs, to confer a survival phenotype for the recipient cell, contributing toward chemoresistance and malignancy. Despite its important role in cancer progression, the molecular mechanisms underlying TNT formation is not well defined. Within the tumour microenvironment (TME) of NSCLC, hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated causing growth, and invasion. In this study, we report a novel crosstalk between HGF/c-Met and β1-integrin involved in the formation of functional TNTs in A549 cells. Through pharmacological inhibitor studies, we discovered Arp2/3 complex, MAPK and PI3K pathways were activated downstream of this crosstalk signalling axis. Furthermore, paxillin was recruited during this key process, localising at the protrusion site of HGF-induced TNTs, and therefore serving as the central link between the upstream and downstream regulators involved. Overall, these results demonstrate a novel strategy to inhibit TNT formation in NSCLC through targeting the HGF/c-Met and β1-integrin signalling axis, thus highlighting the importance of personalised multi-drug targeting in NSCLC.