Mechanics of a multilayer epithelium instruct tumor architecture and function [adult]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA639529 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12016188.fastq.gz | Fastqsanger.gz | |||
| SRR12016189.fastq.gz | Fastqsanger.gz | |||
| SRR12016190.fastq.gz | Fastqsanger.gz | |||
| SRR12016191.fastq.gz | Fastqsanger.gz | |||
| SRR12016192.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 9 |
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Project description:Mechanics of a multilayer epithelium instruct tumor architecture and function
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Project description:Mechanics of a multilayer epithelium instruct tumor architecture and function [E15]
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Project description:Loss of normal tissue architecture is a hallmark of oncogenic transformation. Mechanical forces sculpt tissue architectures during morphogenesis. However, their origins and consequences during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas (BCCs) form ‘buds’, while invasive squamous cell carcinomas (SCC) initiate as ‘folds’. Using computational modeling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumor architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer epithelia. In stratified epidermis, softening and enhanced remodeling of the basement membrane (BM) promote tumor budding, while BM stiffening promotes folding. We show that additional key forces stem from progenitor cell stratification and differentiation Tumor-specific suprabasal stiffness gradients are generated as oncogenic lesions progress toward malignancy, which we computationally predict alter extensile tensions on the tumor BM. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing BM stiffness elevates BM tensions in silico and potentiates invasive SCC progression in vivo. Our findings suggest that mechanical forces, exerted from above and below progenitors of multilayered epithelia, are integrally linked and function to shape premalignant tumor architectures and influence tumor progression.
2020-07-01 | GSE152487 | GEO
Project description:Loss of normal tissue architecture is a hallmark of oncogenic transformation. Mechanical forces sculpt tissue architectures during morphogenesis. However, their origins and consequences during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas (BCCs) form ‘buds’, while invasive squamous cell carcinomas (SCC) initiate as ‘folds’. Using computational modeling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumor architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer epithelia. In stratified epidermis, softening and enhanced remodeling of the basement membrane (BM) promote tumor budding, while BM stiffening promotes folding. We show that additional key forces stem from progenitor cell stratification and differentiation Tumor-specific suprabasal stiffness gradients are generated as oncogenic lesions progress toward malignancy, which we computationally predict alter extensile tensions on the tumor BM. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing BM stiffness elevates BM tensions in silico and potentiates invasive SCC progression in vivo. Our findings suggest that mechanical forces, exerted from above and below progenitors of multilayered epithelia, are integrally linked and function to shape premalignant tumor architectures and influence tumor progression.
2020-07-01 | GSE152486 | GEO
Project description:Loss of normal tissue architecture is a hallmark of oncogenic transformation1. In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis2. However, the origins and consequences of tissue architecture during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas form 'buds', while invasive squamous cell carcinomas initiate as 'folds'. Here, using computational modelling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumour architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer, epithelia. In stratified epidermis, meanwhile, softening and enhanced remodelling of the basement membrane promote tumour budding, while stiffening of the basement membrane promotes folding. Additional key forces stem from the stratification and differentiation of progenitor cells. Tumour-specific suprabasal stiffness gradients are generated as oncogenic lesions progress towards malignancy, which we computationally predict will alter extensile tensions on the tumour basement membrane. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing the stiffness of basement membranes increases membrane tensions in silico and potentiates the progression of invasive squamous cell carcinomas in vivo. Our findings suggest that mechanical forces-exerted from above and below progenitors of multilayered epithelia-function to shape premalignant tumour architectures and influence tumour progression.
| S-EPMC7787055 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-07-01 | GSE152488 | GEO
Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.
2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress
Project description:Changes of inspiration: expiration ration from 1:2 to 1:1 could improve the arterial oxygenation and respiratory mechanics
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Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.
2011-06-27 | E-GEOD-20257 | biostudies-arrayexpress
Project description:While cell mechanics and metastatic potential are related, the molecular factors that drive these behaviors remain unknown. Understanding how molecular signaling networks modulate cellular phenotype and mechanotype can help elucidate how metastasis occurs. Therefore, we developed a workflow to measure mechanical properties and gene expression on the single cell level. The process combines atomic force microscopy and optical microscopy to measure the mechanics and morphology of individual ovarian cancer cells, followed by multiplexed RT-qPCR gene expression analysis. Surprisingly, the genes that most strongly correlated with mechanical properties were not cytoskeletal, but rather were markers of epithelial-to-mesenchymal transition and cancer stemness. A dimensionality reduction analysis showed that cells of different metastatic potential were best identified through combining mechanical and gene expression data. Finally, a network analysis revealed master regulators that can predictably stiffen and soften cells while modulating cell migration. The single cell genomechanics methods demonstrate how molecular drivers can disable biophysical processes underpinning metastasis.
2021-06-01 | GSE154031 | GEO