Cancer cells exhibit hyperactive secretory states that maintain cancer cell viability and remodel the tumor microenvironment. However, the oncogenic signals that heighten secretion remain unclear. Here, we show that p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. p53 loss up-regulates the expression of a Golgi scaffolding protein, progestin and adipoQ receptor 11 (PAQR11), which recruits an adenosine diphosphate ribosylation factor 1–containing protein complex that loads cargos into secretory vesicles. PAQR11-dependent secretion of a protease, PLAU, prevents anoikis and initiates autocrine activation of a PLAU receptor/signal transducer and activator of transcription-3-dependent pathway that up-regulates PAQR11 expression, thereby completing a feedforward loop that amplifies prometastatic effector protein secretion. Pharmacologic inhibition of PLAU receptor impairs the growth and metastasis of p53-deficient cancers. Blockade of PAQR11-dependent secretion inhibits immunosuppressive processes in the tumor microenvironment. Thus, Golgi reprogramming by p53 loss is a key driver of hypersecretion in cancer.

癌细胞表现出过度活跃的分泌状态，维持癌细胞活力并重塑肿瘤微环境。然而，促进分泌的致癌信号仍不清楚。在这里，我们发现 p53 丢失激活高尔基体中的促转移分泌囊泡生物发生。 p53 缺失会上调高尔基体支架蛋白、孕激素和 adipoQ 受体 11 (PAQR11) 的表达，后者会募集含有腺苷二磷酸核糖基化因子 1 的蛋白质复合物，将货物装载到分泌囊泡中。 PAQR11 依赖性蛋白酶 PLAU 分泌可防止失巢凋亡，并启动 PLAU 受体/信号转导器和转录 3 依赖性途径激活剂的自分泌激活，上调 PAQR11 表达，从而完成放大前转移效应蛋白分泌的前馈循环。 PLAU 受体的药理抑制会损害 p53 缺陷型癌症的生长和转移。阻断 PAQR11 依赖性分泌会抑制肿瘤微环境中的免疫抑制过程。因此，p53 丢失导致的高尔基体重编程是癌症分泌过多的关键驱动因素。