EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.
EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.
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DOI：
10.1172/jci165863
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发表时间：
2023-04-03
影响因子：
15.9
通讯作者：
Kurie, Jonathan M.
中科院分区：
文献类型：
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作者：
Tan, Xiaochao;Xiao, Guan-Yu;Wang, Shike;Shi, Lei;Zhao, Yanbin;Liu, Xin;Yu, Jiang;Russell, William K.;Creighton, Chad J.;Kurie, Jonathan M.
恶性肿瘤细胞分泌过多是治疗耐药、转移和临床预后差的基础。然而，恶性高分泌的分子基础仍然不清楚。在这里，我们发现上皮间质转化（EMT）启动了肺癌细胞的胞吐和胞吞囊泡运输程序。EMT激活转录因子锌指E-box结合同源框1（ZEB 1）执行PI 4KIII β至PI 4KII α（PI 4K 2A）依赖性开关，驱动高尔基体和内体中的PI 4P合成。EMT增强了肺癌细胞对PI 4K 2A小分子拮抗剂的脆弱性。PI 4K 2A形成了一个含有MYOIIA的蛋白复合物，促进高尔基体中的分泌囊泡生物合成，从而建立了一个涉及骨桥蛋白（SPP 1）和其他促转移配体的高分泌状态。在内体区室中，PI 4K 2A加速SPP 1受体的再循环以完成SPP 1依赖性自分泌回路，并与HSP 90相互作用以防止AXL受体酪氨酸激酶（细胞迁移的驱动因素）的溶酶体降解。这些结果表明，EMT协调胞吐和胞吞囊泡运输，以建立可治疗的高分泌状态，从而驱动肺癌进展。
Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and poor clinical outcomes. However, the molecular basis for malignant hypersecretion remains obscure. Here, we showed that epithelial-mesenchymal transition (EMT) initiates exocytic and endocytic vesicular trafficking programs in lung cancer. The EMT-activating transcription factor zinc finger E-box–binding homeobox 1 (ZEB1) executed a PI4KIIIβ-to-PI4KIIα (PI4K2A) dependency switch that drove PI4P synthesis in the Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to PI4K2A small-molecule antagonists. PI4K2A formed a MYOIIA-containing protein complex that facilitated secretory vesicle biogenesis in the Golgi, thereby establishing a hypersecretory state involving osteopontin (SPP1) and other prometastatic ligands. In the endosomal compartment, PI4K2A accelerated recycling of SPP1 receptors to complete an SPP1-dependent autocrine loop and interacted with HSP90 to prevent lysosomal degradation of AXL receptor tyrosine kinase, a driver of cell migration. These results show that EMT coordinates exocytic and endocytic vesicular trafficking to establish a therapeutically actionable hypersecretory state that drives lung cancer progression.