Loss of cell–cell adhesion triggers cell migration through Rac1-dependent ROS generation

Abstract

Epithelial cells usually trigger their “migratory machinery” upon loss of adhesion to their neighbors. This default is important for both physiological (e.g., wound healing) and pathological (e.g., tumor metastasis) processes. However, the underlying mechanism for such a default remains unclear. In this study, we used the human head and neck squamous cell carcinoma (HNSCC) SAS cells as a model and found that loss of cell–cell adhesion induced reactive oxygen species (ROS) generation and vimentin expression, both of which were required for SAS cell migration upon loss of cell–cell adhesion. We demonstrated that Tiam1-mediated Rac1 activation was responsible for the ROS generation through NADPH-dependent oxidases. Moreover, the ROS–Src–STAT3 signaling pathway that led to vimentin expression was important for SAS cell migration. The activation of ROS, Src, and STAT3 was also detected in tumor biopsies from HNSCC patients. Notably, activated STAT3 was more abundant at the tumor invasive front and correlated with metastatic progression of HNSCC. Together, our results unveil a mechanism of how cells trigger their migration upon loss of cell–cell adhesion and highlight an important role of the ROS–Src–STAT3 signaling pathway in the progression of HNSCC.

Differentially Expressed Genes, miRNAs and Network Models: A Strategy to Shed Light on Molecular Interactions Driving HNSCC Tumorigenesis

“…The upregulation of ECM-related genes, including collagens and angiogenesis-related ones, suggest the tumor vascularization and aggressiveness [ 55 ]. Conversely, the downregulation of genes associated with the actin cytoskeleton and cell adhesion could be related to tumor cell motility and invasion, contributing to the metastatic potential of HNSCC [ 56 ], an hypothesis further strengthened by the specific upregulation of proteolytic proteins belonging to metalloproteases family [ 57 , 58 ].…”

The influence of spheroid maturity on fusion dynamics and micro-tissue assembly in 3D tumor models

“…The higher level of MMP-3 and CDH-2 enables motility to cells in young spheroids for driving the fusion process. The movement of cells, as shown by the high content of microfilament distribution at the fusion region, triggered by the increase of the ROS level, which is a critical messenger of cellular functions [39][40][41].…”

Quercetin suppresses ROS production and migration by specifically targeting Rac1 activation in gliomas

“…A direct link between the activation of Rac1 and ROS production has been observed. Rac1 showed a direct correlation with ROS to promote cell migration of head and neck squamous cell carcinoma ( Chen Y-H. et al, 2023 ). Apart from this, Rac1 has a role in diverse cellular processes, for example, membrane trafficking [5], hypoxia-stimulated breast cancer cell migration, cell adhesion, and cell proliferation ( Chen M. et al, 2023 ; Bogucka-Janczi et al, 2023 ; Yang et al, 2023 ).…”

“…Rac1 showed a direct correlation with ROS to promote cell migration of head and neck squamous cell carcinoma (Chen Y-H. et al, 2023). Apart from this, Rac1 has a role in diverse cellular processes, for example, membrane trafficking [5], hypoxia-stimulated breast cancer cell migration, cell adhesion, and cell proliferation Bogucka-Janczi et al, 2023;Yang et al, 2023). Rac1 also has a role in cancer initiation, progression, invasion, and metastasis (Zhang et al, 2023).…”