Investigating the role of tetraspanin Tspan15 and ADAM10 in cell invasion and cancer

Abstract

ADAM10 is a ubiquitously expressed transmembrane sheddase involved in the ectodomain shedding of over 100 substrates. The tetraspanin superfamily is an evolutionarily conserved group of transmembrane proteins, which interact with specific partner proteins to regulate their trafficking, lateral mobility, clustering, and signalling. The TspanC8 subgroup of tetraspanins (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) are important regulators of ADAM10, including its substrate specificity, and as such ADAM10 exists as six different ‘molecular scissors’. Further to this, Tspan15 has been reported to promote NF-κB signalling via its interaction with β-TrCP. ADAM10 and Tspan15 have been shown to mediate the invasion of various tumours, and in some malignancies, their role extends to promoting proliferation. However, Tspan15’s role in cancer is not as well characterised as ADAM10’s and very few studies consider the two proteins as a complex. As such, the overarching aim of this thesis was to investigate the role of Tspan15 in cancer and determine whether its mechanism of action is ADAM10-dependent and/or -independent. This thesis provided evidence from the analysis of patient data that ADAM10 and Tspan15 are individually or co-upregulated in a number of cancers, which in some cases is unfavourable for patient survival. However, despite being co-upregulated in pancreatic adenocarcinoma, follow-up in vitro experiments suggested that ADAM10 and Tspan15 do not regulate the invasion or proliferation of this malignancy. In contrast, Tspan15 was shown to promote the invasion of human embryonic kidney HEK-293T cells in an ADAM10-dependent manner, likely through N-cadherin shedding and FGF receptor signalling. Finally, this thesis also provided no evidence to support Tspan15’s involvement in mediating NF-κB signalling, warranting additional follow-up studies. In summary, this work furthers our understanding of the potential role of the Tspan15/ADAM10 ‘molecular scissor’ in tumour progression, and as such could inform the design of future anti-cancer therapeutics