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NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals

The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. Howe...

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Autores principales: Becker-Weimann, Sabine, Xiong, Gaofeng, Furuta, Saori, Han, Ju, Kuhn, Irene, Akavia, Uri-David, Pe'er, Dana, Bissell, Mina J, Xu, Ren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875766/
https://www.ncbi.nlm.nih.gov/pubmed/24243820
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author Becker-Weimann, Sabine
Xiong, Gaofeng
Furuta, Saori
Han, Ju
Kuhn, Irene
Akavia, Uri-David
Pe'er, Dana
Bissell, Mina J
Xu, Ren
author_facet Becker-Weimann, Sabine
Xiong, Gaofeng
Furuta, Saori
Han, Ju
Kuhn, Irene
Akavia, Uri-David
Pe'er, Dana
Bissell, Mina J
Xu, Ren
author_sort Becker-Weimann, Sabine
collection PubMed
description The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (‘acini’), the malignant T4-2 cells that form large tumor-like clusters, and the ‘phenotypically reverted’ T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.
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spelling pubmed-38757662014-01-07 NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals Becker-Weimann, Sabine Xiong, Gaofeng Furuta, Saori Han, Ju Kuhn, Irene Akavia, Uri-David Pe'er, Dana Bissell, Mina J Xu, Ren Oncotarget Research Paper The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (‘acini’), the malignant T4-2 cells that form large tumor-like clusters, and the ‘phenotypically reverted’ T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture. Impact Journals LLC 2013-10-14 /pmc/articles/PMC3875766/ /pubmed/24243820 Text en Copyright: © 2013 Becker-Weimann et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Paper
Becker-Weimann, Sabine
Xiong, Gaofeng
Furuta, Saori
Han, Ju
Kuhn, Irene
Akavia, Uri-David
Pe'er, Dana
Bissell, Mina J
Xu, Ren
NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title_full NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title_fullStr NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title_full_unstemmed NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title_short NFkB disrupts tissue polarity in 3D by preventing integration of microenvironmental signals
title_sort nfkb disrupts tissue polarity in 3d by preventing integration of microenvironmental signals
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875766/
https://www.ncbi.nlm.nih.gov/pubmed/24243820
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