Pancreatic cancer metastasis is transcriptionally regulated by an eleven amino-acid sequence

Introduction: Expression of the integrin alphavbeta6 correlates with increased carcinoma invasion, metastasis and poor survival. The ability of alphavbeta6 to activate latent TGFbeta may lead to the assumption that TGFbeta drives its metastatic propensity. Methods and Results: In syngeneic orthotopic studies of pancreatic ductal adenocarcinoma (PDAC) we have discovered that the c-terminal 11 amino-acids (aa) of the beta6 integrin subunit drives a transcriptional programme that is essential for the maximal metastatic abilities imparted by alphavbeta6 expression, and that it is TGFbeta-independent. Thus compared with alphavbeta6-null PDAC cell lines (TB32043), the alphavbeta6-expressing TB32043b6 increased metastasis to lung by 300% (p<0.05) and to liver by 200%, the latter not quite reaching statistical significance. In contrast cells expressing alphavbeta6 with the c-terminal 11aa of the beta6 subunit deleted (TB32043Δb6) metastasised to lung and liver similarly to the alphavbeta6-null TB32043 cells. RNAseq analysis of tumor tissues revealed the 11aa regulated an 89 gene expression signature correlating with increased metastatic ability. An siRNA library screen of the 49 upregulated genes showed over 50% of genes regulated proliferation and/or 3D invasion. Moreover, pharmacological inhibition of one of the upregulated genes, a SUMO E3 ligase, suppressed the formation of lung metastases but did not affect primary tumor growth. Conclusion: Further analysis of the 11aa-regualted gene signature will reveal additional novel regulators of metastasis of pancreatic and potentially other cancers and could provide novel therapeutic targets for treatment of metastasis.