Abstract
Simple SummaryCancers include a diverse collection of cells harboring distinct molecular signatures with different levels of pro-metastatic activities. This intratumoral heterogeneity and phenotypic plasticity are major causes of targeted therapeutic failure and it should be considered when developing prognostic tests. Through the analysis of the Focal Adhesion Kinase (FAK) protein and the matrix metalloprotease MMP-2, both implicated in multiple steps of the metastatic spectrum, in complex multicellular tumor spheroids we show that cancer cell populations over-expressing MMP-2 or cancer-associated fibroblasts can release FAK-deficient cancer cells from their constrained metastatic fitness. Consistently, MMP-2, not FAK, serves as an independent prognostic factor in head and neck squamous cell carcinomas. Measurement of intratumor heterogeneity facilitate the development of more efficient biomarkers to predict the risk of metastasis and of more-effective personalized cancer therapies.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.
Highlights
Cancer metastasis is the leading cause of cancer-related death and, unraveling the mechanisms of this complex process is an effective approach to increasing our ability to effectively target and treat this disease to decrease patient morbidity and mortality
We have recently set up an in vitro system for the analysis of the collective cell migration of squamous cell carcinoma (SCC) cells in 3D systems [26]. We showed that both mesenchymal N-cadherin-expressing cancer cells and cancer-associated fibroblasts cooperate in collective migration of epithelial cancer cells by leading their collective migration
As recently reported [26], SCC38 and SCC42B cells assembled as multicellular spheroids in collagen matrix migrate as a collective unit following an outwards and downwards direction as observed upon three-dimensional reconstructions of Z-stacked images taken after 24 h of culture (Figure 1A)
Summary
Cancer metastasis is the leading cause of cancer-related death and, unraveling the mechanisms of this complex process is an effective approach to increasing our ability to effectively target and treat this disease to decrease patient morbidity and mortality. Two distinct patterns of tumor cell migration and invasion have been described far: single-cell migration and collective migration of multi-cellular clusters [1,2]. It has become apparent that multi-cellular cluster migration is usually led by a subset of “leader and invasion-competent cells” that show the highest capacity for proteolytic ECM remodeling and induce the collective invasion of otherwise “followers and invasion less-competent” epithelial cells. These interactions are inherently very complex during the collective migration of mechanically coupled cells because of the additional regulation of cell–cell junctional forces transmitted across cadherin adhesions [4,5]. It has become evident that leader cells are the ones that have the highest capacity for proteolytic ECM remodeling via MMP-2 upregulation and redistribution [10]
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