Grant: Project Grant

DICER1 syndrome is a rare, inherited disorder that puts children and young adults at an increased risk of developing cancers in multiple organs, such as lung, kidney, and female reproductive organs. Although each individual cancer type associated with DICER1 is rare, the overall inherited risk affects about 1 in every 4,000 North Americans, making it one of the most common ways to inherit a risk for cancers affecting children and young adults. Better treatments are needed as no effective treatments are available. To achieve this, it is important to understand the biology of these cancers. DICER1 syndrome is caused by a mutation that inactivates one copy of the DICER1 gene, inherited from one of the patient's parents. We previously discovered that cancer development in these patients is accompanied by the acquisition of very specific mutations in the second copy of DICER1 gene. Although useful for diagnostics, this discovery has not, so far, led to significant understanding of the disease development at molecular and cellular level. This is largely due to no reliable disease model being available to study these cancers. To overcome this, our team developed a first-of-its-kind mouse model for these cancers. Like patients, these mice inherit the two defects in Dicer1, causing them to develop kidney cancers that resemble the human disease when viewed under a microscope. Cells from these mouse tumours can be cultured on plastic and regrow into tumors upon being put back into mice. Notably, by simultaneous introduction of a fluorescent protein along with the mutated Dicer1 we can track the development of these tumours. Our team will use these new models, and their derivative cells, to understand how DICER1 mutations precisely and gradually transform normal cells into a less aggressive early cancer, and then progress into an aggressive state. Understanding the whole transformation process will help us design future preventive and treatment strategies for clinical testing.