Tspan8 and CD151 promote metastasis by distinct mechanisms

CD151 and Tspan8 are metastasis-promoting tetraspanins. To define whether Tspan8 and CD151 fulfil redundant or additive activities, Tspan8 and CD151 were stably knocked-down in highly metastatic rat pancreatic adenocarcinoma BSp73ASML cells (ASML(wt), ASML-Tspan8(kd), ASML-CD151(kd)).ASML-CD151(kd) and ASML-Tspan8(kd) cells metastasise via the lymphatics to the lung with delay and a 2-3-fold increased survival time compared to ASML(wt) cells. Yet, CD151 and Tspan8 distinctly contribute to metastasis. Pronounced adhesion of ASML-Tspan8(kd) cells is due to CD151 associating with the alpha3 integrin chain, whereas strikingly increased ASML-CD151(kd) cell motility is efficiently inhibited by anti-beta4. These opposing Tspan8 and CD151 activities are due to distinct beta4 recruitment into Tspan8 complexes, accompanied by beta4 phosporylation, src recruitment, focal adhesion kinase (FAK) and Ras activation. On the other hand, CD151 associates more readily with proteases, particularly matrix metalloproteinase (MMP)13 and MMP9, than Tspan8. The stronger CD151-MMP association is accompanied by pronounced collagen I and IV and laminin111 degradation, also seen in metastatic tissue, and strengthens invasiveness.CD151 and Tspan8 coordinately promote metastasis, where Tspan8 overrides the adhesive features of CD151 by recruiting integrins out of adhesion into motility promoting complexes. CD151 more efficiently than Tspan8 recruiting and activating MMP9 and MMP13 creates a path for migrating tumour cells.