Abstract
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 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 in animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumour cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of novel 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.
Competing Interest Statement
J.D. has acted as a consultant for AstraZeneca, Bayer, Jubilant, Theras, BridgeBio, Vividion and Novartis, and has funded research agreements with Bristol Myers Squibb, Revolution Medicines and Boehringer Ingelheim. E.W.T. is a founder and shareholder in Myricx Pharma Ltd, and receives consultancy or research funding from Kura Oncology, Pfizer Ltd, Samsara Therapeutics, Myricx Pharma Ltd, MSD, Exscientia, and Daiichi Sankyo. All other authors declare no competing interests.
Footnotes
Online author list corrected to add middle initials and special characters. Files uploaded remain unchanged.
