Pro-migratory and TGF-ß-activating functions of αvß6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch.

ABSTRACT

The integrin αvß6 is up-regulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvß6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-ß1; this latter function complicates therapeutic targeting of αvß6, since TGF-ß1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvß6 functions are linked; both require actin cytoskeletal reorganization, and it is suggested that tractive forces generated during cell migration activate TGF-ß1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-ß1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvß6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-ß1 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 αvß6, we found that Eps8 was up-regulated in >70% of PDACs. In complex with Abi1/Sos1, Eps8 regulated αvß6-dependent cell migration through activation of Rac1. Down-regulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvß6-dependent TGF-ß1 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 αvß6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-ß1 activation (Rho-dependent) functional phenotype, respectively. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.