Yohei Hisada

About

My current research interest focuses on the mechanisms of cancer-associated thrombosis. During my graduate studies under the supervision of Dr. Yasuhiro Matsumura, I developed a new method for cancer therapy/diagnosis by targeting fibrin in cancer tissue using a monoclonal antibody produced in our laboratory. This work sparked my interest in the mechanisms of cancer-associated thrombosis. Although the association between cancer and thrombosis is well-known, the mechanisms of how cancer induces thrombosis are still unclear. Therefore, I decided to pursue my postdoctoral research in the laboratory of Dr. Nigel Mackman, who is a world-leading scientist for his work on tumor-derived, tissue factor-positive extracellular vesicles (TF+ EVs). Dr. Mackman and colleagues have shown that levels of TF+ EVs are increased in patients with cancer and there is an association between EV TF activity and venous thrombosis in pancreatic cancer patients. My first study was to determine the contribution of endogenous TF+ EVs from human pancreatic tumors (BxPC-3) in nude mice to venous thrombosis. To do this I established a new mouse model of cancer-associated thrombosis. I found that tumor-bearing mice had increased venous thrombus size in an inferior vena cava stasis model compared with controls. Importantly, I found that selective inhibition of tumor-derived human TF+ EVs significantly reduced thrombus size. This indicates that human TF derived from the tumor enhances thrombosis at a distal site. This work was published in the Journal of Thrombosis and Haemostasis. In the second study, I investigated the roles of neutrophils and neutrophil extracellular traps (NETs) in cancer-associated thrombosis. I found that BxPC-3 orthotopic tumor-bearing mice have elevated plasma levels of granulocyte colony stimulating factor, neutrophil elastase, and citrullinated histone H3, and increased circulating neutrophils. In addition, I detected increased numbers of neutrophils and enhanced NET formation in thrombi from tumor-bearing mice compared with thrombi from controls. Finally, I found that either depletion of neutrophils using anti-Ly6G antibody and degradation of NETs or cell-free DNA using DNase I significantly both reduced thrombus weight in tumor-bearing mice but not in controls. This work was published in Haematologica in 2020. In parallel with these projects, I am developing a syngeneic model of pancreatic cancer-associated thrombosis. This will allow me to use a genetic approach to study the role of different pathways on cancer-associated thrombosis. By understanding the role of different pathways in cancer-associated thrombosis, I hope to develop new therapeutic drugs to safely reduce venous thrombosis in cancer patients Recently, I measured levels of EV TF activity and other coagulation markers in patients with two types of hantavirus infection. Patients with either Sin Nombre Virus or Puumala Orthohantavirus infection showed activation of coagulation. In collaboration with a group in NIH, I also measured levels of EV TF activity in monkeys infected with Ebola virus. Interestingly, Ebola infection strongly increased EV TF activity in monkeys.

Education

Publications