Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Abstract

Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an in vitro mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin β3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.

Beyond proteases: Basement membrane mechanics and cancer invasion

“…Invadopodia use MMP2, MMP9, and MT1-MMP to degrade the BM ( Clark et al, 2007 ; Poincloux et al, 2009 ). Application of mechanical strain onto the surrounding ECM enhances invadopodia maturation and cell invasion ( Gasparski et al, 2017 ). Invadopodia activity is highest at moderate levels of cross-linking in collagen I matrices, compared with much lower or higher cross-linking ( Pourfarhangi et al, 2018 ).…”

Mechanical Cues Affect Migration and Invasion of Cells From Three Different Directions

“…Transient mechanical strain facilitates maturation of invadopodia, elongation of invadopodia and subsequently a pronounced migration and invasion of cells into hydrogels due to this mechanical load (Menon and Beningo, 2011;Gasparski et al, 2017). Hence, enhanced invasion due to this mechanical stimulus necessitates the cells to be invasive by themselves, since non-invasive cells cannot be induced to be invasive.…”

“…As a consequence of encouraging maturation of invadopodia, there is a concomitant enhancement of MMP activity levels linked to invadopodia. Tugging forces have been established as intrinsically supportive of metastatic cell invasion, and they continue to deliver a mechanical stimulus for the foundation of mechanically initiated maturation of invadopodia (Gasparski et al, 2017).…”

The Complicated Body in Motion: Rediscovering the Mechanical Stimulations in Cell Models of Human Disease

“…In vitro experiments have shown that change in stiffness can alter cell proliferation, even promote cancer growth. Adding to the mechanical property of cells, including the cancer cells, the tumor stiffness itself is promoting tumor growth 20 . Ideas have begun to emerge that tumor growth might be affected when the sensory proteins in the cancer cells were inhibited.…”