Figure 3.

Tspan8 promoted tumor progression. (A) Tspan8 acts as a facilitator. This accounts for membrane bound Tspan8, where it strengthens CD44v6, integrin, and cldn7palm/EpCAM complex signaling activity via its association with PKC and PI4K. This also holds true for the Exo-recruited TEM complex described to modulate the ECM, to promote or inhibit angiogenesis and to contribute actively to premetastatic niche formation. (B) Tspan8 is associated with MMP14 and the association of Tspan8 with α6β1 promotes, besides other the transcription of MMP2 and MMP9. Upon proform activation, also assisted by the proximity to CD44v6, matrix proteins become degraded and VEGF is released. VEGF, in collaboration with collagen degradation products, promotes angiogenesis. In addition, a complex between Tspan8, CD44v6, α6β4, and MMP is found in focal contact. The matrix degradation promoted tissue injury contributes to platelet activation and thrombosis, where together with the release of VEGF a positive feedback loop is created further pushing platelet activation and thrombus formation. Full name of proteins are listed in Table S1. With the multitude of Tspan8 associating molecules, we only present one example building on the association with MMP, which strengthens angiogenesis and thrombus formation. However, it should at least be mentioned that Tspan8 also associates with TACE, which strongly affect e.g., the delivery of the NOTCH and the EpCAM ICD, both acting as cotranscription factors.