Alpha-actinin-4 is Required for Amoeboid-type Invasiveness of Melanoma Cells [Glycobiology and Extracellular Matrices]

October 8th, 2014 by Shao, H., Li, S., Watkins, S. C., Wells, A.

Alpha-Actinin-4 (ACTN4), a key regulator of the actin cytoskeleton, is upregulated in melanoma, though its role in melanoma remains speculative. We have discovered that in WM1158, a highly aggressive melanoma cell line, downregulation of ACTN4 by shRNA induces a collagen I-dependent amoeboidal-to-mesenchymal transition. Re-expression of WT ACTN4 but not a truncated mutant lacking its C-terminal tail (1-890) successfully restores the amoeboidal morphology suggesting that the ability to link membrane to cytoskeleton is essential for its function of maintaining cellular morphology. Interestingly, in 3D collagen I gels, ACTN4 KD cells are more polarized compared to cells in which scrambled shRNA is expressed. Surprisingly, ACTN4 KD cells migrate faster on collagen I gel (2D) although these two cell lines migrate similarly on tissue culture. Most important for the tumor cell biology of melanoma, downregulation of ACTN4 significantly reduced invasion into 3D collagen I gels representative of the dermis. Taken together, these findings suggest that ACTN4 plays an important role in maintaining the amoeboidal morphology of invasive melanoma and thus promoting dissemination through collagen-rich matrices.