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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2015
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.
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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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