Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
1
Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
2
Unit of Membrane Traffic and Pathogenesis, Institute Pasteur, 75015 Paris, France
3
CIBERONC, 28029 Madrid, Spain
4
Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work and should be consider as co-first authors.
Cancers 2020, 12(12), 3708; https://doi.org/10.3390/cancers12123708
Received: 17 November 2020 / Accepted: 7 December 2020 / Published: 10 December 2020
(This article belongs to the Section Cancer Pathophysiology)
Simple Summary
Cancers 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.
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Keywords:
metastasis; collective migration; focal adhesion kinase; matrix metallopeptidase 2; cancer-associated fibroblasts; squamous cell carcinomas
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
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MDPI and ACS Style
Sáenz-de-Santa-María, I.; Celada, L.; San José Martínez, A.; Cubiella, T.; Chiara, M.-D. Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2. Cancers 2020, 12, 3708. https://doi.org/10.3390/cancers12123708
AMA Style
Sáenz-de-Santa-María I, Celada L, San José Martínez A, Cubiella T, Chiara M-D. Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2. Cancers. 2020; 12(12):3708. https://doi.org/10.3390/cancers12123708
Chicago/Turabian StyleSáenz-de-Santa-María, Inés; Celada, Lucía; San José Martínez, Andrés; Cubiella, Tamara; Chiara, María-Dolores. 2020. "Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2" Cancers 12, no. 12: 3708. https://doi.org/10.3390/cancers12123708
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