Grant: CIHR Fellowship

Efforts to understand how cancers develop and progress are largely conducted within the framework of a "cell-autonomous" paradigm of cancer. In this view, a cell's genome incurs a mutation that allows it to survive and replicate under changing selective pressures. These pressures come from inside the tumour cell itself (e.g. cell-death signals) and from the tumour cell's immediate environment (e.g. immune system). Development and prescription of drugs targeting those precise alterations form the basis of personalized or precision medicine today. Unfortunately, for most cancer types even when drugs successfully target these alterations, tumours either continue to grow or drug resistance inevitably occurs. Subsequently, improvements to cancer patient survival have been very modest, and for some cancers, like pancreatic cancer, have not improved in decades. Tumours are complex systems, composed of genetically diverse populations of cells (or subclones)-a phenomenon referred to as intratumour heterogeneity. Emerging evidence supports a new paradigm of cancer biology, which states that the interactions between the different cells within (i.e. tumour subclones) and around a tumour (e.g. immune cells) work together to promote tumour growth and evade normal cell-death processes, in a non-cell autonomous manner. A deeper understanding of tumour systems in this context has been impeded by a lack of experimental models that reflect the complex biology of cancer in native organ systems, and that allow for elucidation of cross talk between tumour subclones and supporting cells, in their native environments. The overall goal of this project is to create a biologically relevant model of tumour heteroclonality in the pancreas, and use it to decipher the interactions that drive tumour formation and behaviour. An improved biological understanding of tumour biology in this way is critically required for developing therapeutics that target tumour systems as a whole.