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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis with a 5-year survival rate less than 5% because of its ability to metastasise, its late detection and the lack of effective therapies. The Integrin v{beta}6 is highly overexpressed in PDAC and correlates with poor prognosis. The integrin {beta}6 subunit contains a unique C-terminal tail of 11 amino acids (aa) that regulates downstream signals, although the mechanism remains unclear. Here, using integrin {beta}6-deficient cells lines, we have developed two PDAC mouse models overexpressing the full-length {beta}6 and a mutant {beta}6 lacking the C-terminal 11aa (v{Delta}{beta}6). In vitro, v{beta}6 overexpression increased cell proliferation, migration and invasion in a 3D spheroid model. The elimination of the C-terminal 11aa decreased proliferation and totally impaired cell migration and invasion. v{Delta}{beta}6 cells also expressed reduced MMPs in vitro. In vivo, orthotopic implantation of v{beta}6 overexpressing cells showed decreased overall survival and more spontaneous metastasis compared to v{Delta}{beta}6 and v{beta}6-null cells. Therefore, the C-terminal 11aa of the integrin {beta}6 subunit regulates PDAC progression and metastasis.