The role of protease-activated receptor-1 in pancreatic cancer progression

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal disease with 5-year survival rates of around 10%, and pancreatic cancer-associated mortality is becoming increasingly common over the past years. Despite strenuous research efforts, overall improvement in disease survival is not progressing steadily; therefore, novel therapeutic targets are needed.
Protease-activated receptor-1 (PAR1) is associated with disease progression and poor overall survival in different cancer types. In addition, PAR1 was previously shown to induce tumor growth and chemoresistance in PDAC. This thesis first investigates how PAR1 aids tumor progression and drives mesenchymal phenotypes. Second, in the context of interaction of tumor cells with the tumor microenvironment, particularly with macrophages, specific PAR1 agonists are identified in driving mesenchymal differentiation, and how tumor cells escape the macrophage-induced cell death via this mechanism is given in detail. Third, to extend the understanding of the molecular mechanism of macrophage-induced cell death, a spectrum of macrophages subtypes are investigated in this thesis. A cross-comparison of the expression profiles identified secretory elements that drive this phenomenon. Finally, the tumor cell-macrophage crosstalk through PAR1 activation how this mechanism contributes to acinar-to-ductal metaplasia and pancreatic cell fates is given. In this context, the PAR1 driven cell differentiation from acinar to ductal cells is investigated in early disease models to elucidate the role of PAR1 in the pre-cancerous and early stages of pancreatic cancer.