ADAM8 as a theranostic in PDAC

• Applicants: Professor Dr. Jörg-Walter Bartsch; Dr. Bettina Lehman, since 5/2022
• Subject Area: Gastroenterology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329116008

ADAM8 is a metalloprotease-disintegrin with a proven clinical impact on PDAC. Whereas ADAM8 is a validated target for PDAC tumor cells, its role in tumor-associated cells remains to be established (therapeutics). Tumor-associated macrophages and neutrophils express high levels of ADAM8 in PDAC. We found that stroma derived ADAM8 regulates the expression and activity of different pro-tumorigenic factors such as MMP9, ADAM17 and Lipocalin-2 in tumor cells by EV-mediated signaling in the PDAC microenvironment. We aim for a deeper understanding of ADAM8-dependent communication between tumor cells and neutrophils. Thus, we will analyze the impact of ADAM8 expression in macrophages and neutrophils on tumor progression in vivo by injecting KPC cells into mice with either macrophage (Cx3CR1-Cre) or neutrophil-specific (MRP8-Cre, S100B) Adam8 knockout. Furthermore, we will continue to analyze the impact of ADAM8 on PDAC development by generating KPC mice with global Adam8 deficiency. On the diagnostic side, ADAM8 levels in serum EVs can be utilized as serum biomarker for PDAC progression, and the miRNA cargos of these EVs turn out to be promising biomarkers of FPC and PDAC. A meaningful combination of miRNAs and biomarker proteins will be explored in larger prospective patient cohorts to allow for highest specificity and sensitivity in prediction of pancreatic cancer.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 325: Clinical relevance of tumor-microenvironment interactions in pancreatic cancer
• Ehemaliger Antragsteller: Uwe Schlomann, Ph.D., until 5/2022