How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.

Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have...

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Autores principales:	Justin Werfel, Silva Krause, Ashley G Bischof, Robert J Mannix, Heather Tobin, Yaneer Bar-Yam, Robert M Bellin, Donald E Ingber
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f06e57e54424523ac945a502435ac64
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spelling	oai:doaj.org-article:9f06e57e54424523ac945a502435ac642021-11-18T08:52:37ZHow changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.1932-620310.1371/journal.pone.0076122https://doaj.org/article/9f06e57e54424523ac945a502435ac642013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24098430/?tool=EBIhttps://doaj.org/toc/1932-6203Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1)-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics) to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.Justin WerfelSilva KrauseAshley G BischofRobert J MannixHeather TobinYaneer Bar-YamRobert M BellinDonald E IngberPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e76122 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Justin Werfel Silva Krause Ashley G Bischof Robert J Mannix Heather Tobin Yaneer Bar-Yam Robert M Bellin Donald E Ingber How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
description	Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1)-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics) to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.
format	article
author	Justin Werfel Silva Krause Ashley G Bischof Robert J Mannix Heather Tobin Yaneer Bar-Yam Robert M Bellin Donald E Ingber
author_facet	Justin Werfel Silva Krause Ashley G Bischof Robert J Mannix Heather Tobin Yaneer Bar-Yam Robert M Bellin Donald E Ingber
author_sort	Justin Werfel
title	How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
title_short	How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
title_full	How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
title_fullStr	How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
title_full_unstemmed	How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
title_sort	how changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/9f06e57e54424523ac945a502435ac64
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How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.

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