Pancreatic ductal adenocarcinoma is particularly metastatic, with dismal survival rates and few treatment options. Stiff fibrotic stroma is a hallmark of pancreatic tumours, but how stromal mechanosensing affects metastasis is still unclear. Here, we show that mechanical changes in the pancreatic cancer cell environment affect not only adhesion and migration, but also ATP/ADP and ATP/AMP ratios. Unbiased metabolomic analysis reveals that the creatine–phosphagen ATP-recycling system is a major mechanosensitive target. This system depends on arginine flux through the urea cycle, which is reflected by the increased incorporation of carbon and nitrogen from l-arginine into creatine and phosphocreatine on stiff matrix. We identify that CKB is a mechanosensitive transcriptional target of YAP, and thus it increases phosphocreatine production. We further demonstrate that the creatine–phosphagen system has a role in invasive migration, chemotaxis and liver metastasis of cancer cells.

胰腺导管腺癌尤其具有转移性，生存率低且治疗选择很少。坚硬的纤维化基质是胰腺肿瘤的标志，但基质机械传感如何影响转移仍不清楚。在这里，我们表明胰腺癌细胞环境的机械变化不仅影响粘附和迁移，还影响 ATP/ADP 和 ATP/AMP 比率。无偏代谢组学分析表明，肌酸-磷酸原 ATP 循环系统是主要的机械敏感目标。该系统依赖于通过尿素循环的精氨酸通量，这反映在刚性基质上碳和氮从L-精氨酸到肌酸和磷酸肌酸中的结合增加。我们发现 CKB 是 YAP 的机械敏感转录靶标，因此它可以增加磷酸肌酸的产生。我们进一步证明肌酸-磷酸原系统在癌细胞的侵袭性迁移、趋化性和肝转移中发挥作用。