Elucidating the Molecular Mechanism of FZD5 Essentiality in ​RNF43 ​ mutant Pancreatic Cancer

Abstract Our laboratory recently identified FZD5 as the sole essential FZD, out of ten human FZD receptors, in RNF43 mutant pancreatic cancers. My work explores two hypotheses behind this finding. First, we hypothesized that FZD5 is the preferential RNF43 substrate. Alternatively, FZD5 may preferentially recognize the Wnt ligand involved in PDAC, and as such RNF43 mutations lead to increased activity of this Wnt-Frizzled signalling circuit. I quantified FZD levels in control cells and in cells harbouring a RNF43 mutation and and observed a broad negative regulation role for RNF43 towards FZD receptors. Then I examined the role of FZD5 as the main FZD responsible of transmitting endogenous Wnt signalling in pancreatic cancer. There, I obtained evidence that the N-terminus ligand binding domain of FZD5 was required for the growth of PDAC cells. Together, my work highlights that the FZD5 essentiality can be attributed to preferential FZD receptor-Wnt ligand selectivity.M.Sc