INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY
Journal of Cell Biology Pub Date : 2024-11-04 Epub Date: 2024-08-09 DOI:10.1083/jcb.202401012
Golam T Saffi, Lydia To, Nicholas Kleine, Ché M P Melo, Keyue Chen, Gizem Genc, K C Daniel Lee, Jonathan Tak-Sum Chow, Gun Ho Jang, Steven Gallinger, Roberto J Botelho, Leonardo Salmena
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引用次数: 0

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.

INPP4B通过PIKfyve和TRPML-1介导的溶酶体外渗促进PDAC的侵袭性。
包括胰腺导管腺癌(PDAC)在内的侵袭性实体恶性肿瘤可利用溶酶体外泌来改变肿瘤微环境、增强运动性和促进侵袭性。然而,人们对溶酶体功能在恶性细胞中的分子途径仍然知之甚少。在这项研究中,我们证明了肌醇多磷酸4-磷酸酶II型(INPP4B)在PDAC中的过表达与PDAC的进展有关。我们发现,INPP4B 的过表达会促进溶酶体的外周弥散和外排,从而导致 PDAC 细胞的迁移和侵袭潜力增加。从机理上讲,INPP4B 过表达以 PIKfyve 依赖性方式驱动溶酶体上 PtdIns(3,5)P2 的生成,从而引导 TRPML-1 触发钙离子(Ca2+)的释放。我们的研究发现了一个新的致癌信号轴,它通过调节溶酶体磷酸肌醇的平衡来协调 PDAC 的迁移和侵袭特性,从而从分子角度理解了 INPP4B 过表达在 PDAC 中的预后意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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