Diverse matrix metalloproteinase functions regulate cancer amoeboid migration

Area of Science:

• Cancer Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Rounded-amoeboid cancer cells migrate using actomyosin contractility.
• It was previously thought that rounded-amoeboid cells do not require matrix metalloproteinases (MMPs) for invasion.

Purpose of the Study:

• To compare MMP levels in rounded-amoeboid versus elongated-mesenchymal melanoma cells.
• To investigate the role of MMPs in the invasion of rounded-amoeboid melanoma cells.

Main Methods:

• Quantification of MMP levels in different melanoma cell phenotypes.
• Assessment of collagen degradation by melanoma cells.
• Analysis of MMP-9's role in 3D migration and actomyosin contractility regulation.
• Investigation of MMP-9 regulation by Rho-ROCK and JAK-STAT3 signaling pathways.
• Correlation of MMP-9 expression with melanoma progression and cell morphology in clinical samples.

Main Results:

• Rounded-amoeboid melanoma cells exhibit higher secretion of MMP-13 and MMP-9 compared to elongated-mesenchymal cells.
• Rounded-amoeboid cells show more efficient collagen I degradation.
• MMP-9, via a non-catalytic mechanism involving the CD44 receptor, enhances rounded-amoeboid cell migration by regulating actomyosin contractility.
• MMP-9 levels are upregulated in rounded-amoeboid cells and controlled by ROCK-JAK-STAT3 signaling.
• MMP-9 expression correlates with melanoma progression and is prominent at invasive fronts, associated with cell roundness.

Conclusions:

• Rounded-amoeboid melanoma cells utilize both catalytic and non-catalytic functions of MMPs for invasion.
• MMP-9 plays a critical role in promoting rounded-amoeboid cell migration and invasion through novel non-catalytic mechanisms.
• Findings challenge previous assumptions and highlight MMPs as key players in melanoma cell invasion, irrespective of cell morphology.