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

• Final Report Year: 2025

Final Report Abstract

In this project, significant insights were gained about the role of ADAM8 in tumors and metastases. Throughout the project, it became clear that ADAM8 is present not only in tumor cells but also in immune cells of the tumor microenvironment, where it can play an important role in tumor progression. This is especially evident in the ADAM8-mediated migration of immune cells, primarily neutrophilic granulocytes (neutrophils), which can have a tumor-promoting effect. The effects of ADAM8 in the tumor microenvironment lead to increased expression of the matrix metalloproteinase MMP-9 and the protein SPP1/Osteopontin, which is important for angiogenesis—two key proteins that can be regulated by ADAM8. ADAM8 is localized in extracellular vesicles as an active protease and can transfer the expression of MMP-9 and SPP1 from one cell to another by transporting microRNAs in ADAM8-positive vesicles. We were able to demonstrate that the effects of ADAM8 on tumor progression are less related to the active metalloprotease domain but are instead mediated by the cytoplasmic domain of ADAM8. This insight shifted the focus of the project somewhat, as inhibiting the metalloprotease appeared to be less important than understanding the mechanism by which ADAM8 can mediate intracellular signal transduction. It was shown that the intracellular activity of STAT3 is regulated by ADAM8. This regulation occurs through a miRNA, miR181a-5p, a tumor-suppressor miRNA, whose expression can be directly suppressed by ADAM8. miR181a-5p negatively regulates the expression of NEAT1, a long non-coding RNA. NEAT1 can then influence the stability of STAT3 by directly binding to it, preventing the NEAT1-STAT3 complex from being degraded in the proteasome. Thus, we have described a non-canonical function for an ADAM protease that, in this form and level of detail, was previously unknown.

Publications

• Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cellular and Molecular Life Sciences, 77(2), 331-350.
  Scharfenberg, Franka; Helbig, Andreas; Sammel, Martin; Benzel, Julia; Schlomann, Uwe; Peters, Florian; Wichert, Rielana; Bettendorff, Maximilian; Schmidt-Arras, Dirk; Rose-John, Stefan; Moali, Catherine; Lichtenthaler, Stefan F.; Pietrzik, Claus U.; Bartsch, Jörg W.; Tholey, Andreas & Becker-Pauly, Christoph
  
• Expression levels of the metalloproteinase ADAM8 critically regulate proliferation, migration and malignant signalling events in hepatoma cells. Journal of Cellular and Molecular Medicine, 25(4), 1982-1999.
  Awan, Tanzeela; Babendreyer, Aaron; Mahmood Alvi, Abid; Düsterhöft, Stefan; Lambertz, Daniela; Bartsch, Jörg W.; Liedtke, Christian & Ludwig, Andreas
  
• ADAM 8 as a novel target for doxorubicin delivery to TNBC cells using magnetic thermosensitive liposomes. European Journal of Pharmaceutics and Biopharmaceutics, 158, 390-400.
  Alawak, Mohamad; Abu Dayyih, Alice; Mahmoud, Gihan; Tariq, Imran; Duse, Lili; Goergen, Nathalie; Engelhardt, Konrad; Reddy Pinnapireddy, Shashank; Jedelská, Jarmila; Awak, Muhannad; König, Alexander M.; Brüßler, Jana; Bartsch, Jörg W. & Bakowsky, Udo
  
• Cohort Analysis of ADAM8 Expression in the PDAC Tumor Stroma. Journal of Personalized Medicine, 11(2), 113.
  Jaworek, Christian; Verel-Yilmaz, Yesim; Driesch, Sarah; Ostgathe, Sarah; Cook, Lena; Wagner, Steffen; Bartsch, Detlef K.; Slater, Emily P. & Bartsch, Jörg W.
  
• Discovery of Dimeric Arylsulfonamides as Potent ADAM8 Inhibitors. ACS Medicinal Chemistry Letters, 12(11), 1787-1793.
  Cuffaro, Doretta; Camodeca, Caterina; Tuccinardi, Tiziano; Ciccone, Lidia; Bartsch, Jörg W.; Kellermann, Tanja; Cook, Lena; Nuti, Elisa & Rossello, Armando
  
• Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release In Vitro. Mediators of Inflammation, 2021(1).
  Awan, Tanzeela; Babendreyer, Aaron; Wozniak, Justyna; Alvi, Abid Mahmood; Sterzer, Viktor; Cook, Lena; Bartsch, Jörg W.; Liedtke, Christian; Yildiz, Daniela & Ludwig, Andreas
  
• Extracellular Vesicle-Based Detection of Pancreatic Cancer. Frontiers in Cell and Developmental Biology, 9.
  Verel-Yilmaz, Yesim; Fernández, Juan Pablo; Schäfer, Agnes; Nevermann, Sheila; Cook, Lena; Gercke, Norman; Helmprobst, Frederik; Jaworek, Christian; Pogge von Strandmann, Elke; Pagenstecher, Axel; Bartsch, Detlef K.; Bartsch, Jörg W. & Slater, Emily P.
  
• ADAM8 signaling drives neutrophil migration and ARDS severity. JCI Insight, 7(3).
  Conrad, Catharina; Yildiz, Daniela; Cleary, Simon J.; Margraf, Andreas; Cook, Lena; Schlomann, Uwe; Panaretou, Barry; Bowser, Jessica L.; Karmouty-Quintana, Harry; Li, Jiwen; Berg, Nathaniel K.; Martin, Samuel C.; Aljohmani, Ahmad; Moussavi-Harami, S. Farshid; Wang, Kristin M.; Tian, Jennifer J.; Magnen, Mélia; Valet, Colin; Qiu, Longhui ... & Bartsch, Jörg W.
  
• ADAM8-Dependent Extracellular Signaling in the Tumor Microenvironment Involves Regulated Release of Lipocalin 2 and MMP-9. International Journal of Molecular Sciences, 23(4), 1976.
  Cook, Lena; Sengelmann, Marie; Winkler, Birte; Nagl, Constanze; Koch, Sarah; Schlomann, Uwe; Slater, Emily P.; Miller, Miles A.; von Strandmann, Elke Pogge; Dörsam, Bastian; Preußer, Christian & Bartsch, Jörg W.
  
• The GBM Tumor Microenvironment as a Modulator of Therapy Response: ADAM8 Causes Tumor Infiltration of Tams through HB-EGF/EGFR-Mediated CCL2 Expression and Overcomes TMZ Chemosensitization in Glioblastoma. Cancers, 14(19), 4910.
  Liu, Xiaojin; Huang, Yimin; Qi, Yiwei; Wu, Shiqiang; Hu, Feng; Wang, Junwen; Shu, Kai; Zhang, Huaqiu; Bartsch, Jörg W.; Nimsky, Christopher; Dong, Fangyong & Lei, Ting
  
• The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness. Frontiers in Oncology, 12.
  Schäfer, Agnes; Evers, Lara; Meier, Lara; Schlomann, Uwe; Bopp, Miriam H. A.; Dreizner, Gian-Luca; Lassmann, Olivia; Ben Bacha, Aaron; Benescu, Andreea-Cristina; Pojskic, Mirza; Preußer, Christian; von Strandmann, Elke Pogge; Carl, Barbara; Nimsky, Christopher & Bartsch, Jörg W.
  
• Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice. International Journal of Molecular Sciences, 24(24), 17628.
  Zhao, Kai; Calero-Pérez, Pilar; Bopp, Miriam H. A.; Möschl, Vincent; Pagenstecher, Axel; Mulero-Acevedo, Marta; Vázquez, Mario; Barcia, Carlos; Arús, Carles; Nimsky, Christopher; Rusch, Tillmann; Bartsch, Jörg W. & Candiota, Ana Paula
  
• The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis. Cellular Oncology, 48(2), 391-409.
  Gao, Yutong; Zandieh, Kimia; Zhao, Kai; Khizanishvili, Natalia; Fazio, Pietro Di; Yu, Xiangdi; Schulte, Leon; Aillaud, Michelle; Chung, Ho-Ryun; Ball, Zachary; Meixner, Marion; Bauer, Uta-Maria; Bartsch, Detlef Klaus; Buchholz, Malte; Lauth, Matthias; Nimsky, Christopher; Cook, Lena & Bartsch, Jörg W.