Venous thromboembolism represents the second most frequent cause of death in cancer patients and PDAC exhibits the highest incidence of thrombosis among different malignancies. Hence it is of great interest to reveal the cellular and molecular mechanisms that support the development of thrombosis in patients with PDAC. We plan to clarify how immune cell- as well as tumor-induced blood coagulation regulate pancreatic cancer metastasis, to uncover the role of extracellular vesicles (EV) such as large oncosomes in metastasis and to identify targets for inhibition of cancer-specific thrombosis.

We will perform advanced intravital two-photon videofluorescence microscopy under on line conditions using genetic models of pancreatic cancer developed in the consortium to visualize the intra- and extravascular trajectories of tumor cells and their secreted EV during liver metastasis, including their interactions with intravascular host cells such as inflammatory monocytes and NK cells.

We will dissect the molecular mechanisms promoting microvascular fibrin formation by pancreatic cancer cells and focus in particular on the role of mutations in genes of phospholipid translocating proteins involved in the exposure of plasma membrane phosphatidylethanolamine (PE). Among the candidate mediators are in particular P4-ATpases regulating the intrabilayer exchange of phospholipids.

Also, we plan to uncover the identity of the recruited immune cells triggering host-induced blood coagulation after the initial microcirculatory arrest of the tumor cells and characterize the biophysical properties of the microthrombi generated by them, including the fibrin network densities. The extravasated tumor cells and released particles may interact with specific types of tissue macrophages and reprogram them to foster the development of metastatic foci. The role of the identified molecular mediators of tumor- and immune cell-dependent blood coagulation that are activated during metastasis will be evaluated in different models of deep vein thrombosis to assess their potential as antithrombotic targets.