The Integrin Alpha V Beta 6 Drives Pancreatic Cancer Through Diverse Mechanisms And Represents An Effective Target For Therapy

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin alpha v beta 6 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 beta 6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 x 10(-8)). In two separate cohorts, we showed that over 80% of PDACs expressed alpha v beta 6 protein and that paired metastases retained alpha v beta 6 expression. In vitro, integrin alpha v beta 6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both alpha v beta 6-positive human PDAC xenografts and transgenic mice bearing alpha v beta 6-positive PDAC with the alpha v beta 6 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 TGF beta signalling, fewer alpha SMA-positive myofibroblasts, decreased blood vessel density). These data show that alpha v beta 6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.