Although metastasis is the predominant cause of mortality in patients with cancer, how tumour cells invade to form metastases is not well understood. For a cancer cell to metastasise, it must first invade from sites where most solid tumours originate, the epithelia, the skin that lines our organs, and then trans-differentiate to acquire a malignant phenotype. The prevailing metastasis model suggests that as cells mutate to become cancerous, they first form primary tumours from which accumulate mutations that disrupt these epithelia to become more motile (mesenchymal) cells that can move through the body in a process typically referred to as Epithelial-to-Mesenchymal Transition (EMT). Despite this model, our understanding of how tumour cells invade and transition to become a rogue migratory cell has been hindered by our ability to see this process live in real organisms. To visualise this process live, we have developed the transparent embryonic zebrafish skin as a model for the simple epithelia where cancers form, allowing us to directly film cell invasion. By following oncogenically transformed cells within this transparent skin, we found that cells can invade directly from the epithelium before they become actual cancers and independently from primary tumour masses. To do this, they co-opt a process that normally drives epithelial cell death - a process we discovered- called epithelial cell extrusion. Moreover, oncogenic hijacking of this process not only allows cells to invade and migrate throughout the body, but it also causes the cells to simultaneously pinch off the top of the cell, containing essential components that dictate their epithelial behaviour. Thus, invasion causes these cells to lose epithelial traits and become primordial. These cells then transition to a variety of different, more aggressive cell types that form big internal cell masses, similar to metastatic tumours. In this proposal I investigated how these primordial cells become mesenchymal and aggressive to metastasise.
