Grant: Project Grant

Pancreatic cancer is a devastating disease with very poor patient outcome and limited therapeutic options. Metastasis to distant organs, especially the liver is a common characteristic and is the major cause of mortality. Pancreatic cancer progression is also promoted by inflammation, and the micro-environment of the tumors is associated with poor oxygenation (hypoxia), extensive matrix deposition, and poor infiltration of tumor killing immune cells. Recent studies have shown that neutrophils which accumulate in areas of inflammation promote tumor cell metastasis by producing a Neutrophil extracellular trap (NET) which contains a modified form of DNA. This DNA binds to the tumor cells causing them to become invasive and colonizing distant organs (liver) to form metastases. Recently, the receptor on the tumor cells that binds the neutrophil DNA has been identified and shown to promote the invasive behavior of tumor cells by activating a cellular protein called Integrin Linked Kinase ILK) discovered in my lab in 1996 and shown to be critical for cancer progression. Here we will determine if the molecules and cells involved in this NET/ILK axis of metastasis are present in the blood and tumors (primary and metastases) of pancreatic cancer patients; determine using pancreatic cancer cells and organoids in culture the molecular mechanism for the activation ILK by the NET DNA interaction; evaluate this complex in animal models of pancreatic cancer metastasis; and develop potential novel therapeutic strategies to target this complex.