Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease

Gilbert, Penney M.; Weaver, Valerie M.

doi:10.1016/j.semcdb.2016.09.004

Cited by 50 publications

(36 citation statements)

References 122 publications

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“…Accordingly, the coupling of TGF-β to noncanonical β-catenin (Figure 1F) and AP-1 (Figure 1G; p3TP) activation was dramatically augmented in a manner reminiscent of EMT-induced signaling alterations observed previously in basal-like/TNBCs [4, 24] . Interestingly, EMT-associated events transpired in both culture systems ( i.e., 2D- and 3D-cultures), although the magnitude of EMT response was typically greater in 2D-cultures, suggesting that rigid microenvironments potentiate EMT programs stimulated by TGF-β [25–27] .…”

Section: Resultsmentioning

confidence: 99%

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Tian

Schiemann

2017

JCMT

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Aim Estrogen receptor-α (ER-α) activation drives the progression of luminal breast cancers. Signaling by transforming growth factor-β (TGF-β) typically opposes the actions of ER-α; it also induces epithelial-mesenchymal transition (EMT) programs that promote breast cancer dissemination, stemness, and chemoresistance. The impact of EMT programs on nongenomic ER-α signaling remains unknown and was studied herein. Methods MCF-7 and BT474 cells were stimulated with TGF-β to induce EMT programs, at which point ER-α expression, localization, and nongenomic interactions with receptor tyrosine kinases and MAP kinases (MAPKs) were determined. Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated. Results TGF-β stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced cytoplasmic accumulation of ER-α without altering its expression. Post-EMT cells exhibited (i) elevated expression of EGFR and IGF1R, which together with Src formed cytoplasmic complexes with ER-α; (ii) enhanced coupling of EGF, IGF-1 and estrogen to the activation of MAPKs; and (iii) reduced sensitivity to tamoxifen, an event reversed by administration of small molecule inhibitors against the receptors for TGF-β, EGF, and IGF-1, as well as those against MAPKs. Conclusion EMT stimulated by TGF-β promotes anti-estrogen resistance by activating EGFR-, IGF1R-, and MAPK-dependent nongenomic ER-α signaling.

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Section: Resultsmentioning

confidence: 99%

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Tian

Schiemann

2017

JCMT

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“…Cell shape also has important implications in human diseases like cancer since the shape of a cell and its response to its mechanical environment alter motility and proliferative capacity (Bellas and Chen, 2014;Gilbert and Weaver, 2017). The shape of a cell is the result of a complex and dynamic interaction between its cytoskeleton, the plasma membrane and the extracellular matrix (ECM) (Mogilner and Keren, 2009).…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 4-kinase III beta regulates cell shape, migration and Focal Adhesion number

Law-Vinh

Bilodeau

Jacobsen

2019

Preprint

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Cell shape is regulated by adhesion and by cytoskeletal and membrane proteins. Cell shape, adhesion and motility have a complex relationship and understanding them is important in understanding developmental patterning and diseases such as cancer. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates cell shape, migration and Focal Adhesion number. PI4KIIIβ generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of human breast cancers. PI4KIIIβ and the PI4P it generates regulate a range of cellular functions, among them Golgi structure, fly fertility and Akt signaling. Here we show that loss of PI4KIIIβ expression decreases cell migration and alters cell shape in NIH3T3 fibroblasts. The changes are accompanied by an increase in the number of Focal Adhesions in cells lacking PI4KIIIβ. Furthermore, we find that PI4P-containing vesicles move to the migratory leading-edge during migration and that some of these vesicles tether to and fuse with FA. This suggests a novel regulatory role for PI4KIIIβ in cell adhesion and cell shape maintenance.

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“… Summary The mechanical properties of tissues, which are determined primarily by their extracellular matrix (ECM), are largely stable over time despite continual turnover of ECM constituents 1,2 . These observations imply active homeostasis, where cells sense and adjust rates of matrix synthesis, assembly and degradation to keep matrix and tissue properties within the optimal range.…”

mentioning

confidence: 99%

“…Cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins, and actomyosin. These factors transduce physical forces into biochemical signals that regulate gene expression and cell function 2,3 . Tissues maintain nearly constant physical properties in the face of growth, injury, ECM turnover, and altered external forces (e.g.…”

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confidence: 99%

microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis

Moro

Driscoll

Armero

et al. 2018

Preprint

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The mechanical properties of tissues, which are determined primarily by their 32 extracellular matrix (ECM), are largely stable over time despite continual turnover of 33 ECM constituents 1,2 . These observations imply active homeostasis, where cells sense 34 and adjust rates of matrix synthesis, assembly and degradation to keep matrix and 35 tissue properties within the optimal range. However, the regulatory pathways that 36 mediate this process are essentially unknown 3 . Genome-wide analyses of endothelial 37 cells revealed abundant microRNA-mediated regulation of cytoskeletal, adhesive and 38 extracellular matrix (CAM) mRNAs. High-throughput assays showed co-transcriptional 39 regulation of microRNA and CAM genes on stiff substrates, which buffers CAM 40 expression. Disruption of global or individual microRNA-dependent suppression of CAM 41 genes induced hyper-adhesive, hyper-contractile phenotypes in multiple systems in vitro, 42 and increased tissue stiffness in the zebrafish fin-fold during homeostasis and 43 regeneration in vivo. Thus, a network of microRNAs and CAM mRNAs mediate tissue 44 mechanical homeostasis. 45 46 47 48 Cells sense physical forces, including the stiffness of their ECM, through 49 mechanosensitive integrins, their associated proteins, and actomyosin. These factors 50 transduce physical forces into biochemical signals that regulate gene expression and 51 cell function 2,3 . Tissues maintain nearly constant physical properties in the face of 52growth, injury, ECM turnover, and altered external forces (e.g. from blood pressure, 53 tissue hydration or body weight) 1,4,5 . These effects imply tissue mechanical homeostasis, 54 in which cells sense mechanical loads, due to both external and internal forces, and 55 adjust their rates of matrix synthesis, degradation and organization to keep tissue 56 properties constant. Cell contractility is critical in this process, as it is a key component of 57 both the stiffness-sensing regulatory pathways and of the matrix assembly process that 58 governs resultant matrix properties, including stiffness 2,6 . 59Mechanical homeostasis requires that integrin mechanotransduction pathways 60 mediate negative feedback regulation of the contractile and biosynthetic pathways to 61 maintain optimal tissue stiffness. That is, too soft/low force triggers increased matrix 62 synthesis and contractility, while too stiff/high force triggers the opposite. However, in 63 vitro studies have mainly elucidated positive feedback (or feed forward) circuits, where 64 rigid substrates or high external forces increase actin myosin contraction, focal 65 3 adhesions and ECM synthesis 7 . This type of mechanotransduction signaling often 66 characterizes fibrotic tissues, where sustained contractility and excessive ECM 67 compromise tissue function. Very little is known about negative feedback pathways that 68 are therefore critical to establish proper stiffness/contractility in normal, healthy tissues. 69 MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional le...

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Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease

Cited by 50 publications

References 122 publications

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Phosphatidylinositol 4-kinase III beta regulates cell shape, migration and Focal Adhesion number

microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis

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