Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein SPARC has been robustly associated with poor patient prognosis. However, the precise role of SPARC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein in vitro. This conflicting data has been a barrier to the development of new therapeutic approaches targeting SPARC, despite current interest in stromal-therapy.We show conclusively that SPARC acts directly on cancer cells to promote pancreatic cancer cell proliferation. This contradicts previous in vitro studies, but is consistent with the observed clinical association between SPARC expression and poor patient prognosis. However, depletion of fibronectin switches the activity of SPARC from promoting cancer cell proliferation to growth inhibition and induction of apoptosis. Thus, targeting the interaction between SPARC and fibronectin could be used to turn the highly expressed tumour protein SPARC against the tumour to induce tumour cytotoxicity, and is a novel target for PDAC therapy.

SPARC is a matricellular protein that is involved in both pancreatic cancer and diabetes. It belongs to a wider family of proteins that share structural and functional similarities. Relatively little is known about this extended family, but evidence of regulatory interactions suggests the importance of a holistic approach to their study. We show that Hevin, SPOCKs, and SMOCs are strongly expressed within islets, ducts, and blood vessels, suggesting important roles for these proteins in the normal pancreas, while FSTL-1 expression is localised to the stromal compartment reminiscent of SPARC. In direct contrast to SPARC, however, FSTL-1 expression is reduced in pancreatic cancer. Consistent with this, FSTL-1 inhibited pancreatic cancer cell proliferation. The complexity of SPARC family proteins is further revealed by the detection of multiple cell-type specific isoforms that arise due to a combination of post-translational modification and alternative splicing. Identification of splice variants lacking a signal peptide suggests the existence of novel intracellular isoforms. This study underlines the importance of addressing the complexity of the SPARC family and provides a new framework to explain their controversial and contradictory effects. We also demonstrate for the first time that FSTL-1 suppresses pancreatic cancer cell growth.