Validation of ADAM8 as a therapeutic target in highly invasive tumors and in metastasis

• Applicant: Professor Dr. Jörg-Walter Bartsch
• Subject Area: Cell Biology ; Biochemistry ; Hematology, Oncology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318768680

Therapeutic treatment of highly invasive cancers remains challenging due to infiltrative growth of tumor and early metastasis. ADAM8, a metalloprotease-disintegrin, has been identified as a significant driver of invasive and metastatic growth in neoplasias. In this proposal we aim to understand the role of ADAM8 in the tumor microenvironment of triple-negative breast cancer (TNBC). We will focus on the role of ADAM8 in extracellular vesicles released into the tumor microenvironment by tumor cells to affect immune cells (macrophages, neutrophils) and endothelial cells by regulating their activation and transmigration. ADAM8-dependent EV cargo will be analyzed using proteomics and genomics and will be functionally annotated to immune cell function and endothelial properties. As ADAM8 is essential for neutrophil transmigration through endothelia, we will analyze ADAM8-dependent neutrophil function for instance regulation of Lipocalin-2 expression and extracellular MMP-9 activity. Furthermore, the importance of recently identified interaction with myosin 1f, a regulator of neutrophil mobility, will be analyzed in detail. Since ADAM8-positive neutrophils can be found in brain metastases from TNBC, we further aim to analyze the function of ADAM8 in early metastasis when neutrophils are required for transmigration of tumor cells through endothelial cells to distant sites. Given the significant function of ADAM8 in neutrophils and for tumor growth in general, we propose to obtain an ADAM8 specific inhibitory strategy be either generating monoclonal antibodies and/or monobodies. Suitable candidates will be tested in vivo using a mouse mammary fat pad model in a neoadjuvant and adjuvant therapy scheme. The mode of action of the inhibitors will be characterized by analyzing the impact of ADAM8 inhibition on the biochemical functions as revealed in this proposal.

• DFG Programme: Research Grants