Cell signalling crosstalk between the epidermal growth factor receptor, β1-integrin and the c-Met receptor drives tunneling nanotube formation in lung adenocarcinoma

Banerjee, Salonee (2025) Cell signalling crosstalk between the epidermal growth factor receptor, β1-integrin and the c-Met receptor drives tunneling nanotube formation in lung adenocarcinoma. Doctoral thesis, University of East Anglia.

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Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, with lung adenocarcinoma accounting for over half of all cases. Despite advances in targeted therapies, chemoresistance remains a major challenge, driven by complex alterations in receptor tyrosine kinases (RTK), integrin signalling, and intercellular communication within the tumour microenvironment (TME). Tunneling nanotubes (TNTs), which are F-actin-based structures facilitating long-distance transfer of oncogenic cargo, are an emerging mode of cell-to-cell communication implicated in cancer progression and chemoresistance, though their regulation remains poorly understood. The RTKs c-Met and EGFR, activated by hepatocyte growth factor (HGF) and epidermal growth factor (EGF) respectively, are frequently overexpressed in NSCLC and contribute to tumour aggressiveness. Both receptors independently crosstalk with β1-integrin, but whether they cooperate in a shared pathway to regulate TNT formation is unknown. Given the limitations of standard cancer therapies, alternative and combinatorial treatment strategies are also of clinical interest. This research investigated the signalling crosstalk between EGFR, c-Met, and β1-integrin in TNT formation in A5ti9 lung adenocarcinoma cells, while also exploring the broader implications of nanomedicine, and natural product-based therapies in cancer.

This research revealed a previously unexplored signalling crosstalk between the EGFR, β1-integrin and c-Met receptor in the formation of TNTs in A549 cells. Both HGF and EGF individually, as well as in combination, promoted TNT formation to a similar extent at higher concentrations; however, enhanced responses were observed with combined treatment at lower concentrations, suggesting crosstalk. The TNTs observed in this study were F-actin positive, with the presence of α-tubulin in thicker regions. Inhibitor studies identified that HGF/c-Met and EGF/EGFR signalling converged via the MAPK and PI3K pathways to drive TNT formation. Notably, dual inhibition of EGFR and c-Met was necessary to fully abrogate TNTs induced by simultaneous EGF+HGF stimulation. Furthermore, dual targeting of both receptors or their downstream MAPK/PI3K pathways resulted in a greater inhibition of TNT formation, suggesting potential compensatory signalling between the EGF/EGFR and HGF/c-Met axes. β1-integrin was also identified as a key mediator of TNT formation in response to both HGF, EGF, and EGF+HGF, with evidence of its role in linking receptor signalling to cytoskeletal remodelling via paxillin recruitment and Arp2/3 activation. The study further explored the impact of natural compounds and nanoparticles. Certain natural products demonstrated dual behaviour, where they exerted cytotoxic effects on cancer cells while an acetophenone-based fraction from the Knema membranifolia plant also induced TNT formation, highlighting the complexity of their cellular impact. Additionally, TNTs were shown to facilitate nanoparticle transfer, offering a compelling potential for their exploitation in drug delivery. In summary, this research has primarily characterised the crosstalk between EGFR, c-Met, and β1-integrin as a novel mechanism of TNT formation, which can have significant clinical implications in lung adenocarcinoma and overcoming chemoresistance via triple-targeting strategies. In addition, the identification of the modulatory effects of natural products and TNT-mediated transport of nanoparticles highlight the potential alternative role of TNTs in drug delivery.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Chris White
Date Deposited:	10 Jun 2025 10:24
Last Modified:	10 Jun 2025 10:24
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99423
DOI:

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