Characterization and targeting of cathepsin B and L activity in tumor-associated macrophages during pancreatic cancer development and progression.

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Pancreatic ductal adenocarcinoma (PDAC) is associated with the most appalling prognosis among solid tumors and is characterized by an extensive stroma reaction. Evidence accumulated during recent years has clearly demonstrated that stroma-infiltrating inflammatory cells such as tumor-associated macrophages play an important role in regulating tumor progression and chemoresistance. Tumor-associated macrophages represent a major source of secreted proteases such as the cathepsin family of proteases that have been proposed to mediate tumor progression in pancreatic cancer, although their exact mode of action still needs to be determined. The aim of the proposed collaborative project is to elucidate the impact of macrophage-derived cathepsins, in particular of the cysteine proteases cathepsin B (CTSB) and L (CTSL), in the development and progression of pancreatic cancer in vitro and in vivo. This includes the characterization of the impact of CTSB and CTSL on the macrophage polarization and on the crosstalk between tumor cells and macrophages in vitro using macrophages isolated from CTSB-/- or CTSL-/- mice. Furthermore, we will investigate the effects of macrophage-derived CTSB and CTSL as well as the impact of their therapeutic targeting on pancreatic cancer development and tumor progression as well as their influence in inflammation-driven cancer development and chemoresistance in genetic mouse models of pancreatic cancer.