Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2

Abstract

Metastasis remains a clinically unsolved issue in cancer that is initiated by the acquisition of collective migratory properties of cancer cells. Phenotypic and functional heterogeneity that arise among cancer cells within the same tumor increase cellular plasticity and promote metastasis, however, their impact on collective cell migration is incompletely understood. Here, we show that in vitro collective cancer cell migration depends on FAK and MMP-2 and on the presence of cancer-associated fibroblasts (CAFs). The absence of functional FAK rendered cancer cells incapable of invading the surrounding stroma. However, CAFs and cancer cells over-expressing MMP-2 released FAK-deficient cells from this constraint by taking the leader positions in the invasive tracks, pushing FAK-deficient squamous cell carcinoma (SCC) cells towards the stroma and leading to the transformation of non-invasive cells into invasive cells. Our cell-based studies and the RNAseq data from the TCGA cohort of patients with head and neck squamous cell carcinomas reveal that, although both FAK and MMP-2 over-expression are associated with epithelial–mesenchymal transition, it is only MMP-2, not FAK, that functions as an independent prognostic factor. Given the significant role of MMP-2 in cancer dissemination, targeting of this molecule, better than FAK, presents a more promising opportunity to block metastasis.

Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy

“…Table 1 summarises the main studies that revealed the correlations between MMP expression and clinical parameters mainly by collecting TCGA data. The results obtained support the roles of some MMPs as diagnostic, prognostic and therapeutic biomarkers in HNC patients [ 44 , 45 , 46 , 47 , 48 , 49 ].…”

“…Table 1 summarises the main studies that revealed the correlations between MMP expression and clinical parameters mainly by collecting TCGA data. The results obtained support the roles of some MMPs as diagnostic, prognostic and therapeutic biomarkers in HNC patients [44][45][46][47][48][49]. TCGA: The Cancer Genome Atlas; HNSCC: head and neck squamous cell carcinoma; FAK: focal adhesion kinase; PLAU1: urokinase-type plasminogen activator.…”

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

“…The role of matrix-metalloproteinases (MMPs) on the stimulation of invasion and angiogenesis is well established [54]. It has been shown that MMP-9 and MMP-2 released from CAFs can stimulate the potential of invasion and migration in carcinoma cells [55,56]. Through our invasion model, we demonstrated the migration inhibitory effect of CAFs.…”

Focal-adhesion kinase regulates the sialylation of N-glycans via the PI4KIIα-PI4P pathway

“…FAK participates in the integrin-mediated formation of adhesion plaque, which regulates cell adhesion and migration. FAK KO suppresses the cell migration of fibroblasts ( 43 ). In addition, the previous excellent study clearly shows that sialylation of β1 integrin plays an important role in cell migration ( 44 ).…”