Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
Division of General Thoracic Surgery, Inselspital, Bern University Hospital, 3008 Bern, Switzerland.
Sci Adv. 2020 Oct 30;6(44). doi: 10.1126/sciadv.abb9200. Print 2020 Oct.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked fibrosis and low immunogenicity, features that are linked to treatment resistance and poor clinical outcomes. Therefore, understanding how PDAC regulates the desmoplastic and immune stromal components is of great clinical importance. We found that acyl-CoA synthetase long-chain 3 (ACSL3) is up-regulated in PDAC and correlates with increased fibrosis. Our in vivo results show that knockout hinders PDAC progression, markedly reduces tumor fibrosis and tumor-infiltrating immunosuppressive cells, and increases cytotoxic T cell infiltration. This effect is, at least in part, due to decreased plasminogen activator inhibitor-1 (PAI-1) secretion from tumor cells. Accordingly, expression in PDAC positively correlates with markers of fibrosis and immunosuppression and predicts poor patient survival. We found that PAI-1 pharmacological inhibition strongly enhances chemo- and immunotherapeutic response against PDAC, increasing survival of mice. Thus, our results unveil ACSL3-PAI-1 signaling as a requirement for PDAC progression with druggable attributes.
胰腺导管腺癌（PDAC）的特征是明显的纤维化和低免疫原性，这些特征与治疗耐药和临床预后不良有关。因此，了解 PDAC 如何调节纤维母细胞和免疫基质成分具有重要的临床意义。我们发现酰基辅酶 A 合成酶长链 3（ACSL3）在 PDAC 中上调，并与纤维化增加相关。我们的体内结果表明，ACSL3 基因敲除可阻碍 PDAC 的进展，显著减少肿瘤纤维化和肿瘤浸润性免疫抑制细胞，并增加细胞毒性 T 细胞浸润。这种作用至少部分是由于肿瘤细胞中纤溶酶原激活物抑制剂-1（PAI-1）的分泌减少所致。因此，在 PDAC 中，ACSL3 的表达与纤维化和免疫抑制的标志物呈正相关，并预测患者预后不良。我们发现，PAI-1 的药理学抑制可显著增强对 PDAC 的化疗和免疫治疗反应，提高小鼠的存活率。因此，我们的研究结果揭示了 ACSL3-PAI-1 信号通路是 PDAC 进展的必要条件，具有可药物治疗的特性。
