Abstract：
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.
摘要：
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，促进侵袭性。然而,溶酶体功能在恶性细胞中通过的分子途径仍然知之甚少.在这项研究中,我们证明肌醇多磷酸4-磷酸酶，PDAC中II型(INPP4B)过表达与PDAC进展相关。我们表明INPP4B过表达促进溶酶体的外周分散和胞吐作用，导致PDAC细胞的迁移和侵袭潜力增加。机械上,INPP4B过表达以PIKfyve依赖性方式驱动溶酶体上PtdIns(3,5)P2的产生，这指导TRPML-1触发钙离子（Ca2+）的释放。我们的发现通过发现一种新的致癌信号轴，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过表达的预后意义提供了分子理解。
