胞吐
细胞生物学
内体
生物
内吞作用
运动性
癌症研究
分泌物
受体
生物化学
细胞内
作者
Golam T. Saffi,Lydia To,Nicholas Kleine,Ché M.P. Melo,K Chen,Gizem Genc,K.C. Daniel Lee,Jonathan Tak-Sum Chow,Gun Ho Jang,Steven Gallinger,Roberto J. Botelho,Leonardo Salmena
标识
DOI:10.1083/jcb.202401012
摘要
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.
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