Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch

The integrin alpha v beta 6 is up-regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. alpha v beta 6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-beta 1; this latter function complicates therapeutic targeting of alpha v beta 6, since TGF-beta 1 has both tumour-promoting and -suppressive effects. It is unclear how these different alpha v beta 6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF-beta 1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-beta 1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are alpha v beta 6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-beta 1 activation depending on the presence or absence of epidermal growth factor receptor pathway substrate 8 (Eps8), a regulator of actin remodelling, endocytosis, and GTPase activation. Similar to alpha v beta 6, we found that Eps8 was up-regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated alpha v beta 6-dependent cell migration through activation of Rac1. Down-regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing alpha v beta 6-dependent TGF-beta 1 activation. This latter effect was modulated through increased cell tension, regulated by Rho activation. Thus, the Eps8/Abi1/Sos1 tricomplex acts as a key molecular switch altering the balance between Rac1 and Rho activation; its presence or absence in PDAC cells modulates alpha v beta 6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-beta 1 activation (Rho-dependent) functional phenotype, respectively. (C) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.