Abstract
Simple SummaryDetachment of cancer cells is the first step in tumor metastasis and malignancy. Our results showed that the TGF-β1/vimentin/focal adhesion protein assembly axis was involved in the control of the dynamics of initial tumor detachment under adequate nutrition, based on the Boyden chamber and 3D in-gel spheroid analysis. Detachment of cancer cells is the first step in tumor metastasis and malignancy. However, studies on the balance of initial tumor anchoring and detachment are limited. Herein, we revealed that the regulation of cytoskeleton proteins potentiates tumor detachment. The blockage of TGF-β1 using neutralizing antibodies induced cancer cell detachment in the Boyden chamber and 3D in-gel spheroid models. Moreover, treatment with latrunculin B, an actin polymerization inhibitor, enhanced cell dissociation by abolishing actin fibers, indicating that TGF-β1 mediates the formation of actin stress fibers, and is likely responsible for the dynamics of anchoring and detachment. Indeed, latrunculin B disrupted the formation of external TGF-β1-induced actin fibers and translocation of intracellular vinculin, a focal adhesion protein, resulting in the suppression of cell adhesion. Moreover, the silencing of vimentin substantially reduced cell adhesion and enhanced cell detachment, revealing that cell adhesion and focal adhesion protein translocation stimulated by TGF-β1 require vimentin. Using the 3D in-gel spheroid model, we found that latrunculin B suppressed the cell adhesion promoted by external TGF-β1, increasing the number of cells that penetrated the Matrigel and detached from the tumor spheres. Thus, cytoskeleton remodeling maintained the balance of cell anchoring and detachment, and the TGF-β1/vimentin/focal adhesion protein assembly axis was involved in the control dynamics of initial tumor detachment.
Highlights
Mechanotransduction, the conversion of mechanical stimuli into cellular signals, promotes cytoskeleton remodeling and regulates gene expression, which contributes to the cells responding appropriately to the environment
These results suggest that external TGF-β1 increased actin stress fibers and vimentin intermediate filament networks of invasive leading cells after migration
Our study found that cytoskeletal protein remodeling mediated by TGF-β1 and vimentin affected the balance of cell adhesion and dissociation in human colorectal, lung, and pancreatic cancer cell lines (Figures 2 and 5–7)
Summary
Mechanotransduction, the conversion of mechanical stimuli into cellular signals, promotes cytoskeleton remodeling and regulates gene expression, which contributes to the cells responding appropriately to the environment. Cytoskeletal remodeling transduces external mechanical signals into internal responses [1,2]. Cells and the external environment are connected through the cytoskeleton, which transmits external signals to influence cell behavior, including cell protrusion, adhesion, invasion, and metastasis [3]. After the cytoskeleton receives external stimulation, it activates the adhesion protein (focal adhesion kinase, FAK), the migration proteins (small GTP binding protein: RhoA, Cdc, and Rac1), and the proliferation pathway (Hippo Pathway, JAK/STAT, and PI3K-AKT pathways) [4]. Studies on the balance of mechanical transduction in cancer treatment are scarce. Understanding the correlation between pathological mechanical forces and signaling pathways in metastatic cancer can provide different therapeutic strategies
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