Ectopic expression of DOCK8 regulates lysosome-mediated pancreatic tumor cell invasion
Omar L. Gutierrez-Ruiz,
Katherine M. Johnson,
Eugene W. Krueger,
Roseanne E. Nooren,
Nicole Cruz-Reyes,
Carrie Jo Heppelmann,
Tara L. Hogenson,
Martin E. Fernandez-Zapico,
Mark A. McNiven,
Gina L. Razidlo
Affiliations
Omar L. Gutierrez-Ruiz
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Katherine M. Johnson
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Eugene W. Krueger
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
Roseanne E. Nooren
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Nicole Cruz-Reyes
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Carrie Jo Heppelmann
Endocrine Research, Mayo Clinic, Rochester, MN 55905, USA
Tara L. Hogenson
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
Martin E. Fernandez-Zapico
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
Mark A. McNiven
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author
Gina L. Razidlo
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author
Summary: 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.
