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

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 develo...

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Autores principales: Sáenz-de-Santa-María, Inés, Celada, Lucía, San José Martínez, Andrés, Cubiella, Tamara, Chiara, María-Dolores
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764466/
https://www.ncbi.nlm.nih.gov/pubmed/33321813
http://dx.doi.org/10.3390/cancers12123708
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author Sáenz-de-Santa-María, Inés
Celada, Lucía
San José Martínez, Andrés
Cubiella, Tamara
Chiara, María-Dolores
author_facet Sáenz-de-Santa-María, Inés
Celada, Lucía
San José Martínez, Andrés
Cubiella, Tamara
Chiara, María-Dolores
author_sort Sáenz-de-Santa-María, Inés
collection PubMed
description 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. 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.
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spelling pubmed-77644662020-12-27 Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2 Sáenz-de-Santa-María, Inés Celada, Lucía San José Martínez, Andrés Cubiella, Tamara Chiara, María-Dolores Cancers (Basel) Article 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. 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. MDPI 2020-12-10 /pmc/articles/PMC7764466/ /pubmed/33321813 http://dx.doi.org/10.3390/cancers12123708 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sáenz-de-Santa-María, Inés
Celada, Lucía
San José Martínez, Andrés
Cubiella, Tamara
Chiara, María-Dolores
Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title_full Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title_fullStr Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title_full_unstemmed Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title_short Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2
title_sort blockage of squamous cancer cell collective invasion by fak inhibition is released by cafs and mmp-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764466/
https://www.ncbi.nlm.nih.gov/pubmed/33321813
http://dx.doi.org/10.3390/cancers12123708
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