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

Lena Cook1, Marie Sengelmann1, Birte Winkler1

  • 1Department of Neurosurgery, Philipps University Marburg, Baldingerstr, 35033 Marburg, Germany.

International Journal of Molecular Sciences
|February 26, 2022
PubMed

Insights

ADAM8 protease is crucial in pancreatic cancer progression and the tumor microenvironment. Its presence in extracellular vesicles influences cell communication, with macrophage signaling impacting ADAM8-dependent pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • ADAM8 (a metalloprotease-disintegrin) is highly expressed in pancreatic cancer, suggesting a role in tumor progression and cell-cell communication within the tumor microenvironment (TME).
  • ADAM8 expression is found in both tumor cells and immune cells like macrophages within the TME.

Purpose of the Study:

  • To investigate the role of ADAM8 in the TME by analyzing extracellular vesicle (EV) release from ADAM8 knockout (KO) pancreatic ductal adenocarcinoma (PDAC) cells.
  • To understand how macrophage signaling influences ADAM8 expression and associated molecules in PDAC cells.

Main Methods:

  • Generation of ADAM8 knockout PDAC tumor cells.
  • Analysis of extracellular vesicles (EVs) released by wild-type and ADAM8 KO cells.
  • Co-culture experiments with PDAC cells and THP-1 macrophages.
  • Assessment of LCN2 and MMP-9 expression and association with ADAM8 in EVs.

Main Results:

  • ADAM8 is present as an active protease in EVs and associates with lipocalin 2 (LCN2) and matrix metalloprotease 9 (MMP-9) in an ADAM8-dependent manner.
  • ADAM8 sorting into EVs is independent of TSG101.
  • Co-culture with macrophages induced LCN2 and MMP-9 expression in ADAM8 KO cells, indicating macrophage signaling can modulate PDAC cell pathways.
  • MMP-9 regulation by macrophages was independent of M1/M2 polarization, while LCN2 expression was preferentially affected by M1-like macrophages.

Conclusions:

  • ADAM8 exerts a systemic effect within the tumor microenvironment.
  • The expression of ADAM8 in different cell types within the TME is critical and must be considered for effective ADAM8-targeted cancer therapies.
Keywords:
ADAM8MMP-9PDACextracellular vesicleslipocalin 2regulationtumor microenvironment

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