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1.
Cell ; 187(12): 3072-3089.e20, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38781967

RESUMO

Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.


Assuntos
Matriz Extracelular , Mucosa Intestinal , Animais , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/citologia , Matriz Extracelular/metabolismo , Miosina Tipo II/metabolismo , Mesoderma/metabolismo , Mesoderma/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Morfogênese , Metaloproteinases da Matriz/metabolismo
2.
Annu Rev Cell Dev Biol ; 32: 527-554, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27298087

RESUMO

Mechanical force modulates development, influences tissue homeostasis, and contributes to disease. Forces sculpt tissue-level behaviors and direct cell fate by engaging mechanoreceptors and by altering organization of the cytoskeleton and actomyosin contractility to stimulate mechanotransduction mechanisms that alter transcription. Nevertheless, how force specifically leverages mechanotransduction pathways to control transcriptional regulation of cell fate remains unclear. Here we review recent findings specifically in the context of epithelial-to-mesenchymal transitions that have revealed conserved mechanisms whereby extracellular force, mediated through cell-extracellular matrix and cell-cell junctional complexes, induces transcriptional reprogramming to alter cell and tissue fate. We focus on the interplay between tissue mechanics and the epithelial-to-mesenchymal transitions that occur during embryonic development and cancer malignancy. We describe the adhesion-linked cellular machinery that mediates mechano-transduction and elaborate on how these force-linked networks stimulate key transcriptional programs that induce an epithelial-to-mesenchymal phenotypic transition, thereby providing an overview of how mechanical signals can be translated into a change in cell fate.


Assuntos
Desenvolvimento Embrionário , Transição Epitelial-Mesenquimal , Mecanotransdução Celular , Neoplasias/patologia , Animais , Retroalimentação Fisiológica , Humanos , Transdução de Sinais
3.
Genes Dev ; 35(13-14): 963-975, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34168038

RESUMO

Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia.


Assuntos
Células Estromais , Microambiente Tumoral , Animais , Autofagia/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Fibroblastos/metabolismo , Humanos , Camundongos , Microambiente Tumoral/genética
4.
Proc Natl Acad Sci U S A ; 121(20): e2322688121, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38709925

RESUMO

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Glicocálix , Quinolinas , Receptor ErbB-2 , Células Estromais , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Glicocálix/metabolismo , Animais , Linhagem Celular Tumoral , Células Estromais/metabolismo , Células Estromais/patologia , Quinolinas/farmacologia , Camundongos , Comunicação Celular , Técnicas de Cocultura , Mucina-1/metabolismo , Mucina-1/genética , Transdução de Sinais , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores
5.
EMBO J ; 41(17): e109205, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35880301

RESUMO

Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with reconstituted basement membrane in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging a reconstituted basement membrane in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with decreased cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized basement membrane membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function and underscore the importance of tissue mechanics in organoid homeostasis.


Assuntos
Actinas , Retículo Endoplasmático , Actinas/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Filaminas/metabolismo , Fenótipo
6.
Nat Rev Mol Cell Biol ; 15(12): 771-85, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25370693

RESUMO

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.


Assuntos
Matriz Extracelular/química , Matriz Extracelular/metabolismo , Animais , Membrana Basal/química , Membrana Basal/metabolismo , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/metabolismo , Humanos , Neurônios/citologia , Proteoglicanas/metabolismo
7.
Genes Dev ; 32(3-4): 244-257, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29483153

RESUMO

The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1+/+ mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1-/- mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1-/- mice and higher branching by their isolated organoids. When we crossed DDR1-/- mice with MMTV-PyMT mice, the PyMT/DDR1-/- mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90+CD24+ cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14+ basal cells, including K8+K14+ cells, were increased adjacent to necrotic fields. These data suggest that the absence of DDR1 provides a growth and adhesion advantage that favors the expansion of basal cells, potentiates fibrosis, and enhances necrosis/hypoxia and basal differentiation of transformed cells to increase their aggression and metastatic potential.


Assuntos
Receptor com Domínio Discoidina 1/genética , Neoplasias Mamárias Experimentais/patologia , Animais , Neoplasias da Mama/metabolismo , Hipóxia Celular , Receptor com Domínio Discoidina 1/metabolismo , Intervalo Livre de Doença , Células Epiteliais/metabolismo , Feminino , Fibrose , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/genética , Camundongos
8.
Nature ; 573(7774): 421-425, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31511693

RESUMO

Early human embryonic development involves extensive lineage diversification, cell-fate specification and tissue patterning1. Despite its basic and clinical importance, early human embryonic development remains relatively unexplained owing to interspecies divergence2,3 and limited accessibility to human embryo samples. Here we report that human pluripotent stem cells (hPSCs) in a microfluidic device recapitulate, in a highly controllable and scalable fashion, landmarks of the development of the epiblast and amniotic ectoderm parts of the conceptus, including lumenogenesis of the epiblast and the resultant pro-amniotic cavity, formation of a bipolar embryonic sac, and specification of primordial germ cells and primitive streak cells. We further show that amniotic ectoderm-like cells function as a signalling centre to trigger the onset of gastrulation-like events in hPSCs. Given its controllability and scalability, the microfluidic model provides a powerful experimental system to advance knowledge of human embryology and reproduction. This model could assist in the rational design of differentiation protocols of hPSCs for disease modelling and cell therapy, and in high-throughput drug and toxicity screens to prevent pregnancy failure and birth defects.


Assuntos
Âmnio/embriologia , Camadas Germinativas/embriologia , Modelos Biológicos , Células-Tronco Pluripotentes/citologia , Âmnio/citologia , Diferenciação Celular , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Feminino , Camadas Germinativas/citologia , Humanos , Gravidez , Linha Primitiva/citologia
9.
Cell ; 139(5): 891-906, 2009 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19931152

RESUMO

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM remodeling to cancer is appreciated; the relevance of stiffening is less clear. We found that breast tumorigenesis is accompanied by collagen crosslinking, ECM stiffening, and increased focal adhesions. Induction of collagen crosslinking stiffened the ECM, promoted focal adhesions, enhanced PI3 kinase (PI3K) activity, and induced the invasion of an oncogene-initiated epithelium. Inhibition of integrin signaling repressed the invasion of a premalignant epithelium into a stiffened, crosslinked ECM and forced integrin clustering promoted focal adhesions, enhanced PI3K signaling, and induced the invasion of a premalignant epithelium. Consistently, reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence. These data show how collagen crosslinking can modulate tissue fibrosis and stiffness to force focal adhesions, growth factor signaling and breast malignancy.


Assuntos
Neoplasias da Mama/patologia , Matriz Extracelular/metabolismo , Integrinas/metabolismo , Envelhecimento , Animais , Colágeno/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Feminino , Fibrose/patologia , Genes ras , Humanos , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína-Lisina 6-Oxidase/metabolismo , Transdução de Sinais
10.
Nat Rev Mol Cell Biol ; 12(5): 308-19, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21508987

RESUMO

All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.


Assuntos
Matriz Extracelular/fisiologia , Homeostase/fisiologia , Junções Intercelulares/fisiologia , Mecanotransdução Celular/fisiologia , Animais , Adesão Celular/fisiologia , Humanos , Modelos Biológicos , Estresse Mecânico
11.
Nat Mater ; 20(4): 548-559, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33257795

RESUMO

Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Colágeno/metabolismo , Células Estromais/metabolismo , Macrófagos Associados a Tumor/metabolismo , Adulto , Biópsia , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Pessoa de Meia-Idade , Proteína-Lisina 6-Oxidase/metabolismo , Células Estromais/patologia
12.
14.
Nature ; 511(7509): 319-25, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-25030168

RESUMO

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function.


Assuntos
Glicocálix/metabolismo , Glicoproteínas/metabolismo , Integrinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Mama/citologia , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Fibroblastos , Glicocálix/química , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Integrinas/química , Camundongos , Terapia de Alvo Molecular , Mucina-1/metabolismo , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes , Ligação Proteica , Receptores de Superfície Celular
15.
Semin Cell Dev Biol ; 67: 141-152, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27641825

RESUMO

Human tissues are remarkably adaptable and robust, harboring the collective ability to detect and respond to external stresses while maintaining tissue integrity. Following injury, many tissues have the capacity to repair the damage - and restore form and function - by deploying cellular and molecular mechanisms reminiscent of developmental programs. Indeed, it is increasingly clear that cancer and chronic conditions that develop with age arise as a result of cells and tissues re-implementing and deregulating a selection of developmental programs. Therefore, understanding the fundamental molecular mechanisms that drive cell and tissue responses is a necessity when designing therapies to treat human conditions. Extracellular matrix stiffness synergizes with chemical cues to drive single cell and collective cell behavior in culture and acts to establish and maintain tissue homeostasis in the body. This review will highlight recent advances that elucidate the impact of matrix mechanics on cell behavior and fate across these length scales during times of homeostasis and in disease states.


Assuntos
Neoplasias da Mama/genética , Caderinas/genética , Proteínas Contráteis/genética , Células Epiteliais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Mecanotransdução Celular , Adaptação Fisiológica , Animais , Fenômenos Biomecânicos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/metabolismo , Proteínas Contráteis/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Células Epiteliais/citologia , Transição Epitelial-Mesenquimal , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Adesões Focais/metabolismo , Adesões Focais/ultraestrutura , Regulação da Expressão Gênica , Homeostase , Humanos , Glândulas Mamárias Humanas/citologia , Estresse Mecânico
16.
J Cell Sci ; 130(1): 71-82, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28043968

RESUMO

All cells sense and integrate mechanical and biochemical cues from their environment to orchestrate organismal development and maintain tissue homeostasis. Mechanotransduction is the evolutionarily conserved process whereby mechanical force is translated into biochemical signals that can influence cell differentiation, survival, proliferation and migration to change tissue behavior. Not surprisingly, disease develops if these mechanical cues are abnormal or are misinterpreted by the cells - for example, when interstitial pressure or compression force aberrantly increases, or the extracellular matrix (ECM) abnormally stiffens. Disease might also develop if the ability of cells to regulate their contractility becomes corrupted. Consistently, disease states, such as cardiovascular disease, fibrosis and cancer, are characterized by dramatic changes in cell and tissue mechanics, and dysregulation of forces at the cell and tissue level can activate mechanosignaling to compromise tissue integrity and function, and promote disease progression. In this Commentary, we discuss the impact of cell and tissue mechanics on tissue homeostasis and disease, focusing on their role in brain development, homeostasis and neural degeneration, as well as in brain cancer.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Matriz Extracelular/metabolismo , Homeostase , Animais , Fenômenos Biomecânicos , Humanos , Mecanotransdução Celular , Microambiente Tumoral
17.
Phys Biol ; 15(2): 026002, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29116056

RESUMO

Thermal fluctuations in cell membranes manifest as an excess area ([Formula: see text]) which governs a multitude of physical process at the sub-micron scale. We present a theoretical framework, based on an in silico tether pulling method, which may be used to reliably estimate [Formula: see text] in live cells. We perform our simulations in two different thermodynamic ensembles: (i) the constant projected area and (ii) the constant frame tension ensembles and show the equivalence of our results in the two. The tether forces estimated from our simulations compare well with our experimental measurements for tethers extracted from ruptured GUVs and HeLa cells. We demonstrate the significance and validity of our method by showing that all our calculations performed in the initial tether formation regime (i.e. when the length of the tether is comparable to its radius) along with experiments of tether extraction in 15 different cell types collapse onto two unified scaling relationships mapping tether force, tether radius, bending stiffness κ, and membrane tension σ. We show that [Formula: see text] is an important determinant of the radius of the extracted tether, which is equal to the characteristic length [Formula: see text] for [Formula: see text], and is equal to [Formula: see text] for [Formula: see text]. We also find that the estimated excess area follows a linear scaling behavior that only depends on the true value of [Formula: see text] for the membrane, based on which we propose a self-consistent technique to estimate the range of excess membrane areas in a cell.


Assuntos
Membrana Celular/fisiologia , Simulação por Computador , Modelos Biológicos , Termodinâmica
19.
Cancer Metastasis Rev ; 35(4): 655-667, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27914000

RESUMO

The extracellular matrix (ECM) is a guiding force that regulates various developmental stages of the breast. In addition to providing structural support for the cells, it mediates epithelial-stromal communication and provides cues for cell survival, proliferation, and differentiation. Perturbations in ECM architecture profoundly influence breast tumor progression and metastasis. Understanding how a dysregulated ECM can facilitate malignant transformation is crucial to designing treatments to effectively target the tumor microenvironment. Here, we address the contribution of ECM mechanics to breast cancer progression, metastasis, and treatment resistance and discuss potential therapeutic strategies targeting the ECM.


Assuntos
Neoplasias da Mama/patologia , Transformação Celular Neoplásica/patologia , Matriz Extracelular/patologia , Animais , Humanos , Neoplasias Mamárias Experimentais/patologia , Metástase Neoplásica
20.
Hepatology ; 64(1): 261-75, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26755329

RESUMO

UNLABELLED: Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. CONCLUSION: Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275).


Assuntos
Matriz Extracelular/fisiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/fisiologia , Animais , Células Cultivadas , Citoesqueleto/fisiologia , Expressão Gênica , Cirrose Hepática/metabolismo , Mecanotransdução Celular , Camundongos Endogâmicos C57BL , Microscopia de Força Atômica , Quinases Associadas a rho/metabolismo
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