Wnt secretion, trafficking and pathway activation: towards a structure-based understanding (360G-Wellcome-203732_Z_16_A)

In recent years of cancer research, significant focus has been dedicated to the definition of the so-called "hallmarks of cancer", i.e. common alterations underlying and unifying the apparent diversity of this extremely multifaceted, complex and heterogeneous disease. A recurrent theme identified both in early setting of tumour initiation - particularly in relation with maintenance of cancer stem cells - as well as in advanced and metastatic settings, relates to alterations in the Wnt pathway. This is a pivotal signalling way controlling growth and body organization in the embryo; in the adult life, it governs tissue regeneration and homeostasis in a tightly regulated manner. My aim is to investigate the events involved in the activation phase of the signalling cascade, with a special attention to the mechanisms of secretion and extracellular trafficking of the activating ligand (the Wnt protein itself). I will do that using the tools of structural biology, in particular x-ray crystallography and, where applicable, cryo-EM. Coupled with a detailed functional analysis based on the structural findings, the work will help shedding light on a so-far unclear molecular picture, in turn enhancing the options for a targeted modulation of the pathway for therapeutic purposes.