增强的溶酶体活性是胰腺导管腺癌（PDAC）的一个特征，由KRAS致癌基因协调介导肿瘤生长和转移，尽管该现象的机制尚不清楚。通过比较蛋白质组学研究，我们发现致癌基因KRAS显著富集溶酶体上的鸟苷核苷酸交换因子（GEF）细胞分裂动力蛋白8（DOCK8）。令人惊讶的是，在PDAC的子集中，DOCK8异常表达，在体外和体内促进细胞侵袭。DOCK8与溶酶体相互结合，调节溶酶体形态和运动性，DOCK8的丢失导致溶酶体尺寸增大。DOCK8促进溶酶体表面的肌动蛋白聚合，同时增加溶酶体蛋白酶卡特普西嗪B的蛋白酶活性。关键是，DOCK8的消耗显著减少了卡特普西嗪依赖的细胞外基质降解，并且削弱了PDAC细胞的侵袭能力。这些发现表明DOCK8的异位表达是KRAS驱动的溶酶体调节和胰腺癌细胞侵袭的关键推动因素。版权所有 © 2023 The Authors. Elsevier Inc.发表. 版权所有

Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor growth and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) on lysosomes. Surprisingly, DOCK8 is aberrantly expressed in a subset of PDAC, where it promotes cell invasion in vitro and in vivo. DOCK8 associates with lysosomes and regulates lysosomal morphology and motility, with loss of DOCK8 leading to increased lysosome size. DOCK8 promotes actin polymerization at the surface of lysosomes while also increasing the proteolytic activity of the lysosomal protease cathepsin B. Critically, depletion of DOCK8 significantly reduces cathepsin-dependent extracellular matrix degradation and impairs the invasive capacity of PDAC cells. These findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation and invasion in pancreatic cancer cells.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.