Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis
Goran Tomić,
Clare Sheridan,
Alice Y. Refermat,
Marc P. Baggelaar,
James Sipthorp,
Bhuvana Sudarshan,
Cory A. Ocasio,
Alejandro Suárez-Bonnet,
Simon L. Priestnall,
Eleanor Herbert,
Edward W. Tate,
Julian Downward
Affiliations
Goran Tomić
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Clare Sheridan
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Alice Y. Refermat
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Marc P. Baggelaar
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, 80 Wood Lane, London W12 0BZ, UK
James Sipthorp
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, 80 Wood Lane, London W12 0BZ, UK
Bhuvana Sudarshan
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Cory A. Ocasio
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Alejandro Suárez-Bonnet
The Royal Veterinary College, Department of Pathobiology & Population Sciences, Hawkshead Lane, Hatfield AL9 7TA, UK; Experimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Simon L. Priestnall
The Royal Veterinary College, Department of Pathobiology & Population Sciences, Hawkshead Lane, Hatfield AL9 7TA, UK; Experimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Eleanor Herbert
The Royal Veterinary College, Department of Pathobiology & Population Sciences, Hawkshead Lane, Hatfield AL9 7TA, UK; Experimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Edward W. Tate
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, 80 Wood Lane, London W12 0BZ, UK
Julian Downward
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Corresponding author
Summary: Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo short hairpin RNA (shRNA) screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals and animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumor cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC.
