Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis.

中文翻译：

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INPP4B 通过 PIKfyve 和 TRPML-1 介导的溶酶体胞吐作用促进 PDAC 侵袭性。


侵袭性实体恶性肿瘤，包括胰腺导管腺癌（PDAC），可以利用溶酶体胞吐作用来改变肿瘤微环境、增强运动性并促进侵袭性。然而，恶性细胞中溶酶体功能的分子途径仍然知之甚少。在这项研究中，我们证明 PDAC 中肌醇多磷酸 4-磷酸酶 II 型 (INPP4B) 过度表达与 PDAC 进展相关。我们发现 INPP4B 过表达促进溶酶体的外周分散和胞吐作用，从而增加 PDAC 细胞的迁移和侵袭潜力。从机制上讲，INPP4B 过表达以 PIKfyve 依赖性方式驱动溶酶体上 PtdIns(3,5)P2 的生成，从而指导 TRPML-1 触发钙离子 (Ca2+) 的释放。我们的研究结果通过发现一种新型致癌信号轴，通过调节溶酶体磷酸肌醇稳态来协调 PDAC 的迁移和侵袭特性，为 PDAC 中 INPP4B 过度表达的预后意义提供了分子理解。