2. Academic Validation
  3. ADAM8-Dependent Extracellular Signaling in the Tumor Microenvironment Involves Regulated Release of Lipocalin 2 and MMP-9

ADAM8-Dependent Extracellular Signaling in the Tumor Microenvironment Involves Regulated Release of Lipocalin 2 and MMP-9

  • Int J Mol Sci. 2022 Feb 10;23(4):1976. doi: 10.3390/ijms23041976.
Lena Cook 1,  Marie Sengelmann 1,  Birte Winkler 1,  Constanze Nagl 1,  Sarah Koch 1,  Uwe Schlomann 1 2,  Emily P Slater 2,  Miles A Miller 3,  Elke Pogge von Strandmann 4,  Bastian Dörsam 4,  Christian Preußer 4,  Jörg W Bartsch 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Philipps University Marburg, Baldingerstr, 35033 Marburg, Germany.
  • 2 Department of Visceral Surgery, Philipps University Marburg, Baldingerstr, 35033 Marburg, Germany.
  • 3 Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
  • 4 Department of Medicine, Institute for Tumor Immunology, Philipps University Marburg, 35043 Marburg, Germany.
PMID: 35216088 DOI: 10.3390/ijms23041976
Abstract

The metalloprotease-disintegrin ADAM8 is critically involved in the progression of pancreatic Cancer. Under malignant conditions, ADAM8 is highly expressed and could play an important role in cell-cell communication as expression has been observed in tumor and immune cells of the tumor microenvironment (TME) such as macrophages. To analyze the potential role of ADAM8 in the TME, ADAM8 knockout PDAC tumor cells were generated, and their release of extracellular vesicles (EVs) was analyzed. In EVs, ADAM8 is present as an active protease and associated with lipocalin 2 (LCN2) and matrix metalloprotease 9 (MMP-9) in an ADAM8-dependent manner, as ADAM8 KO cells show a lower abundance of LCN2 and MMP-9. Sorting of ADAM8 occurs independent of TSG101, even though ADAM8 contains the recognition motif PTAP for the ESCRTI protein TSG101 within the cytoplasmic domain (CD). When tumor cells were co-cultured with macrophages (THP-1 cells), expression of LCN2 and MMP-9 in ADAM8 KO cells was induced, suggesting that macrophage signaling can overcome ADAM8-dependent intracellular signaling in PDAC cells. In co-culture with macrophages, regulation of MMP-9 is independent of the M1/M2 polarization state, whereas LCN2 expression is preferentially affected by M1-like macrophages. From these data, we conclude that ADAM8 has a systemic effect in the tumor microenvironment, and its expression in distinct cell types has to be considered for ADAM8 targeting in tumors.

Keywords

ADAM8; MMP-9; PDAC; extracellular vesicles; lipocalin 2; regulation; tumor microenvironment.

Figures