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Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization
During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity f...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695340/ https://www.ncbi.nlm.nih.gov/pubmed/26670048 http://dx.doi.org/10.1016/j.celrep.2015.11.025 |
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author | del Pozo Martin, Yaiza Park, Danielle Ramachandran, Anassuya Ombrato, Luigi Calvo, Fernando Chakravarty, Probir Spencer-Dene, Bradley Derzsi, Stefanie Hill, Caroline S. Sahai, Erik Malanchi, Ilaria |
author_facet | del Pozo Martin, Yaiza Park, Danielle Ramachandran, Anassuya Ombrato, Luigi Calvo, Fernando Chakravarty, Probir Spencer-Dene, Bradley Derzsi, Stefanie Hill, Caroline S. Sahai, Erik Malanchi, Ilaria |
author_sort | del Pozo Martin, Yaiza |
collection | PubMed |
description | During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization. |
format | Online Article Text |
id | pubmed-4695340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46953402016-01-31 Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization del Pozo Martin, Yaiza Park, Danielle Ramachandran, Anassuya Ombrato, Luigi Calvo, Fernando Chakravarty, Probir Spencer-Dene, Bradley Derzsi, Stefanie Hill, Caroline S. Sahai, Erik Malanchi, Ilaria Cell Rep Article During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization. Cell Press 2015-12-06 /pmc/articles/PMC4695340/ /pubmed/26670048 http://dx.doi.org/10.1016/j.celrep.2015.11.025 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article del Pozo Martin, Yaiza Park, Danielle Ramachandran, Anassuya Ombrato, Luigi Calvo, Fernando Chakravarty, Probir Spencer-Dene, Bradley Derzsi, Stefanie Hill, Caroline S. Sahai, Erik Malanchi, Ilaria Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title | Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title_full | Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title_fullStr | Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title_full_unstemmed | Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title_short | Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization |
title_sort | mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695340/ https://www.ncbi.nlm.nih.gov/pubmed/26670048 http://dx.doi.org/10.1016/j.celrep.2015.11.025 |
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