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

Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch
Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch
The integrin αvβ6 is upregulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganisation, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 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 αvβ6, we found that Eps8 was upregulated in >70% of PDAC. In complex with Abi1/Sos1, Eps8 regulated αvβ6-dependent cell migration through activation of Rac1. Downregulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6-dependent TGF-β1 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 αvβ6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-β1 activation (Rho-dependent) functional phenotype respectively.
37-50
Tod, Joanne
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Hanley, Christopher
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Morgan, Mark R.
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Rucka, Marta
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Mellows, Toby
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Lopez, Maria-Antoinette
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Kiely, Philip
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Moutasim, Karwan
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Frampton, Steven, James
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Sabnis, Durgagauri
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Fine, David R.
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Johnson, Colin
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Marshall, John F.
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Scita, Giorgio
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Jenei, Veronika
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Thomas, Gareth
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Tod, Joanne
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Hanley, Christopher
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Morgan, Mark R.
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Rucka, Marta
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Mellows, Toby
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Lopez, Maria-Antoinette
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Kiely, Philip
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Moutasim, Karwan
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Frampton, Steven, James
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Sabnis, Durgagauri
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Fine, David R.
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Johnson, Colin
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Marshall, John F.
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Scita, Giorgio
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Jenei, Veronika
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Thomas, Gareth
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Tod, Joanne, Hanley, Christopher, Morgan, Mark R., Rucka, Marta, Mellows, Toby, Lopez, Maria-Antoinette, Kiely, Philip, Moutasim, Karwan, Frampton, Steven, James, Sabnis, Durgagauri, Fine, David R., Johnson, Colin, Marshall, John F., Scita, Giorgio, Jenei, Veronika and Thomas, Gareth (2017) Pro-migratory and TGF-β-activating functions of αvβ6 integrin in pancreatic cancer are differentially regulated via an Eps8-dependent GTPase switch. The Journal of Pathology, 243 (1), 37-50. (doi:10.1002/path.4923).

Record type: Article

Abstract

The integrin αvβ6 is upregulated in numerous carcinomas, where expression commonly correlates with poor prognosis. αvβ6 promotes tumour invasion, partly through regulation of proteases and cell migration, and is also the principal mechanism by which epithelial cells activate TGF-β1; this latter function complicates therapeutic targeting of αvβ6, since TGF-β1 has both tumour-promoting and -suppressive effects. It is unclear how these different αvβ6 functions are linked; both require actin cytoskeletal reorganisation, and it is suggested that tractive forces generated during cell migration activate TGF-β1 by exerting mechanical tension on the ECM-bound latent complex. We examined the functional relationship between cell invasion and TGF-β1 activation in pancreatic ductal adenocarcinoma (PDAC) cells, and confirmed that both processes are αvβ6-dependent. Surprisingly, we found that cellular functions could be biased towards either motility or TGF-β1 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 αvβ6, we found that Eps8 was upregulated in >70% of PDAC. In complex with Abi1/Sos1, Eps8 regulated αvβ6-dependent cell migration through activation of Rac1. Downregulation of Eps8, Sos1 or Rac1 suppressed cell movement, while simultaneously increasing αvβ6-dependent TGF-β1 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 αvβ6-dependent functions, resulting in a pro-migratory (Rac1-dependent) or a pro-TGF-β1 activation (Rho-dependent) functional phenotype respectively.

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Accepted/In Press date: 24 May 2017
e-pub ahead of print date: 13 June 2017
Published date: September 2017
Organisations: Cancer Sciences, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 411916
URI: https://eprints.soton.ac.uk/id/eprint/411916
PURE UUID: 45232a80-a0ff-4a03-828e-1c38e743afec
ORCID for Christopher Hanley: ORCID iD orcid.org/0000-0003-3816-7220

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Date deposited: 29 Jun 2017 16:31
Last modified: 10 Dec 2019 05:58

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Contributors

Author: Joanne Tod
Author: Christopher Hanley ORCID iD
Author: Mark R. Morgan
Author: Marta Rucka
Author: Toby Mellows
Author: Maria-Antoinette Lopez
Author: Philip Kiely
Author: Karwan Moutasim
Author: Steven, James Frampton
Author: Durgagauri Sabnis
Author: David R. Fine
Author: Colin Johnson
Author: John F. Marshall
Author: Giorgio Scita
Author: Veronika Jenei
Author: Gareth Thomas

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