Research Overview.

• Molecular mechanisms underlying intracellular signalling activated by the Wnt and Hedgehog families of secreted growth factors.
  
  To fully understand the cellular signalling mechanisms underlying the Wnt and Hedgehog pathways, we integrate proteomic and genome-wide CRISPR functional genomic techniques with traditional biochemistry and cell biology approaches to reveal new genes involved in these pathways in different cellular contexts. We are interested in the defects found within these pathways contributing to human diseases such as cancer. The role of Wnt proteins in differentiation of human pluripotent stem cells towards various lineages and in morphogenesis of 3D organoid cultures is also an area of investigation. (Mis et al. J Cell Biol 2020; Rajakulendran et al. Genes and Dev 2019)

• Development of new therapeutics targeting developmental pathways.
  
  In collaboration with the group of Sachdev Sidhu at the Donnelly Centre, we have developed therapeutic antibodies modulating Wnt signalling that are now under clinical evaluation. We plan to continue optimize second generation molecules that are safer and more effective as well as identify novel antibodies that block new targets in the Wnt pathway. Recently, we contributed to the development of a new antibody modality that enables activation of Wnt signalling pathways with complete selectivity. We are testing these molecules for regenerative medicine applications such as directed differentiation of progenitor stem cells for cell therapies and direct mobilization of tissue stem cells for endogenous repair. (Chidiac et al. EMBO Mol Med 2021; Tao et al. Elife 2019; Steinhart et al. Nature Medicine 2017)

  

• Deciphering the molecular wiring of high fatality cancers using functional genomic screens.

  Glioblastoma and pancreatic ductal adenocarcinomas are two cancers with especially poor prognosis and limited treatment options. Using genome-wide CRISPR-Cas9 functional and phenotypic screens performed in patient-derived cancer stem cells, we are identifying genes that 1) are essential for the growth of these cancers 2) block their normal differentiation 3) underlie tumour heterogeneity. We are also performing chemogenomic screens to identify mechanisms of drug resistance and genes conferring hypersensitivity to standard of care therapeutic drugs. (Richards et al. Nature Cancer 2021; Macleod et al. Cell Reports 2019)