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.

中文翻译：

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纤连蛋白可作为分子开关确定SPARC在胰腺癌中的功能。

胰腺导管腺癌（PDAC）是所有实体瘤中最致命的一种，迫切需要更有效的治疗方法。人们认为基质在肿瘤的发展和转移中起着至关重要的作用，基质细胞蛋白SPARC的高基质表达与不良的患者预后密切相关。但是，SPARC的确切作用一直存在争议，多项研究表明该蛋白在体外具有肿瘤抑制特性。尽管当前对基质疗法有兴趣，但这些矛盾的数据已成为开发针对SPARC的新治疗方法的障碍。我们得出结论，SPARC直接作用于癌细胞以促进胰腺癌细胞的增殖。这与以前的体外研究相矛盾，但与观察到的SPARC表达与不良患者预后之间的临床关联是一致的。然而，纤连蛋白的消耗将SPARC的活性从促进癌细胞增殖转变为生长抑制和凋亡诱导。因此，靶向SPARC和纤连蛋白之间的相互作用可用于使高表达的肿瘤蛋白SPARC对抗肿瘤以诱导肿瘤细胞毒性，并且是PDAC治疗的新靶标。