The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

TY - JOUR

T1 - The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

AU - Reader, Claire S.

AU - Vallath, Sabari

AU - Steele, Colin W.

AU - Haider, Syed

AU - Brentnall, Adam

AU - Desai, Ami

AU - Moore, Kate M.

AU - Jamieson, Nigel B.

AU - Chang, David

AU - Bailey, Peter

AU - Scarpa, Aldo

AU - Lawlor, Rita

AU - Chelala, Claude

AU - Keyse, Stephen M.

AU - Biankin, Andrew

AU - Morton, Jennifer P.

AU - Evans, T. R. Jeffry

AU - Barry, Simon T.

AU - Sansom, Owen J.

AU - Kocher, Hemant M.

AU - Marshall, John F.

N1 - © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

PY - 2019/11

Y1 - 2019/11

N2 - Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10 −8). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10 −8). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6-positive human PDAC xenografts and transgenic mice bearing αvβ6-positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.

KW - 264RAD

KW - PDAC

KW - cancer

KW - integrin

KW - mouse model

KW - pancreas

KW - transgenic

KW - αvβ6

KW - alpha v beta 6

UR - https://www.scopus.com/pages/publications/85071885128

U2 - 10.1002/path.5320

DO - 10.1002/path.5320

M3 - Article

C2 - 31259422

SN - 0022-3417

VL - 249

SP - 332

EP - 342

JO - Journal of Pathology

JF - Journal of Pathology

IS - 3

ER -