Project title: Understanding the physiologically relevant functions of DAXX

Outcomes:

Cancers arise from DNA mutations that alter the properties of the cell, allowing for uncontrolled cell growth and tumor development. DNA mutations have been profiled in many different cancers, including pancreatic neuroendocrine tumors (PanNETs). Remarkably, the mutations in PanNETs are different than other cancers and we currently do not understand how these mutations lead to disease. This knowledge is essential to develop new therapies.

Our work focuses specifically on DAXX and ATRX, genes with DNA mutations in approximately 43% of PanNETs. Because mouse models have been essential for research understanding the relevant functions of genes, we have created a new mouse model that allows us to remove DAXX from all cells in the pancreas. With this model we have thoroughly explored the normal functions of DAXX and evaluated what happens when DAXX is lost. We demonstrate that DAXX plays an important role when the pancreas is stressed or injured. The loss of DAXX impairs the ability of the pancreas to recover and return to normal. This is because DAXX maintains the general structure and regulation of DNA in the cell, which ultimately controls what proteins are present and how the cells and tissue behave. Our current work investigates this role in greater detail. We are combining state of the art DNA analysis with our existing and three additional new mouse lines to deepen our understanding of DAXX biology and the consequences of DAXX mutations. We are currently completing similar studies to understand ATRX function(s) using mouse models. Our early data suggest that DAXX and ATRX can both work together and independently in the pancreas. Combined, these studies continue to advance our understanding of how mutations in DAXX and ATRX lead to PanNETs and will provide the foundation for future work to identify new treatments for these cancers.

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