MassIVE MSV000091036

Partial Public PXD039351

DOCK8 is a Novel Regulator of Lysosome Mediated Pancreatic Cancer Invasion

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Description

Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor progression 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) DOCK8 on lysosomes. Surprisingly, we found that DOCK8 is aberrantly expressed in a subset of PDAC where it promotes cell invasion and proliferation. Further, DOCK8 associates with lysosomes and regulates lysosomal morphology and motility. DOCK8 promotes actin polymerization at the surface of lysosomes, while increasing the levels and proteolytic activity of the lysosomal protease cathepsin B. Depletion of DOCK8 significantly reduces extracellular matrix degradation and impairs the invasive capacity of PDAC cells. Further, CRISPR-based knockout of DOCK8 dramatically reduces tumor size and metastasis in vivo. Together, these findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation, tumor progression, and metastasis. [doi:10.25345/C5K931G73] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Metastasis, invasion, pancreatic cancer, lysosome, matrix degradation

Contact

Principal Investigators:
(in alphabetical order) 		Gina L Razidlo, Mayo Clinic, USA
Submitting User: carriejo
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