Transglutaminase stabilizes melanoma adhesion under laminar flow

Area of Science:

• Biophysics
• Cell Biology
• Biochemistry

Background:

• Metastatic melanoma cells must adhere to extracellular matrix proteins under blood flow to survive.
• Fibronectin (FN) is a key subendothelial matrix protein involved in cell adhesion.
• Transglutaminase-catalyzed cross-linking may stabilize these adhesive contacts.

Purpose of the Study:

• To investigate the role of transglutaminase in melanoma cell adhesion under wall shear stress (WSS).
• To determine the effect of transglutaminase inhibitors on melanoma cell adhesion thresholds.
• To elucidate the mechanism of transglutaminase-mediated stabilization of cell-FN interactions.

Main Methods:

• Assessing human melanoma cell adhesion to immobilized fibronectin under varying WSS.
• Measuring wall shear adhesion threshold (WSAT) and wall shear detachment threshold (WSDeT).
• Utilizing transglutaminase inhibitors (monodansylcadaverine, INO-3178) in flow and static adhesion assays.
• Analyzing the formation of cross-linked fibronectin complexes.

Main Results:

• Melanoma cells adhered rapidly and resisted high WSS on fibronectin.
• Transglutaminase inhibitors significantly reduced WSAT and WSDeT, promoting cell detachment.
• Inhibitors prevented the formation of cross-linked fibronectin, indicating impaired matrix stabilization.
• Static assays confirmed dose-dependent inhibition of cell adhesion by transglutaminase inhibitors.

Conclusions:

• Transglutaminase-catalyzed cross-linking is critical for stabilizing melanoma cell adhesion to fibronectin under WSS.
• Inhibiting transglutaminase activity disrupts melanoma cell adhesion and promotes detachment.
• This mechanism is a potential therapeutic target for preventing melanoma metastasis.