Dataset Information

Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes.

ABSTRACT: Matrix stiffness that is sensed by a cell or measured by a purely physical probe reflects the intrinsic elasticity of the matrix and also how thick or thin the matrix is. Here, mesenchymal stem cells (MSCs) and their nuclei spread in response to thickness-corrected matrix microelasticity, with increases in nuclear tension and nuclear stiffness resulting from increases in myosin-II and lamin-A,C. Linearity between the widely varying projected area of a cell and its nucleus across many matrices, timescales, and myosin-II activity levels indicates a constant ratio of nucleus-to-cell volume, despite MSCs' lineage plasticity. Nuclear envelope fluctuations are suppressed on the stiffest matrices, and fluctuation spectra reveal a high nuclear tension that matches trends from traction force microscopy and from increased lamin-A,C. Transcriptomes of many diverse tissues and MSCs further show that lamin-A,C's increase with tissue or matrix stiffness anti-correlates with lamin-B receptor (LBR), which contributes to lipid/sterol biosynthesis. Adipogenesis (a soft lineage) indeed increases LBR:lamin-A,C protein stoichiometry in MSCs versus osteogenesis (stiff). The two factors compete for lamin-B in response to matrix elasticity, knockdown, myosin-II inhibition, and even constricted migration that disrupts and segregates lamins in situ. Matrix stiffness-driven contractility thus tenses the nucleus to favor lamin-A,C accumulation and suppress soft tissue phenotypes.

SUBMITTER: Buxboim A

PROVIDER: S-EPMC5687034 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes.

Buxboim Amnon A Irianto Jerome J Swift Joe J Athirasala Avathamsa A Shin Jae-Won JW Rehfeldt Florian F Discher Dennis E DE

Molecular biology of the cell 20170920 23

Matrix stiffness that is sensed by a cell or measured by a purely physical probe reflects the intrinsic elasticity of the matrix and also how thick or thin the matrix is. Here, mesenchymal stem cells (MSCs) and their nuclei spread in response to thickness-corrected matrix microelasticity, with increases in nuclear tension and nuclear stiffness resulting from increases in myosin-II and lamin-A,C. Linearity between the widely varying projected area of a cell and its nucleus across many matrices, t ...[more]

PMID: 28931598

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Project description:BACKGROUND:In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. METHODS:We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. RESULTS:We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. CONCLUSIONS:As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.

Dataset Information

Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes.

Publications

Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes.

Similar Datasets

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