Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mechanical confinement governs phenotypic plasticity in melanoma [HMGB2OE_RNAseq]

ABSTRACT: Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes - proliferative versus invasive states. While it has long been hypothesised that such switching is triggered by external cues, the identity of these cues has remained elusive. Here, we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of these rare cells showed flattened, elliptical nuclei suggestive of mechanical confinement by nearby adjacent tissue. Spatial and single-cell transcriptomics demonstrated that the interface cells adopted a gene program of neuronal invasion, including acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism for phenotype switching in melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253801 | GEO | 2024/01/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Mechanical confinement governs phenotypic plasticity in melanoma [HMGB2OE_ATACseq]

Project description:Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes - proliferative versus invasive states. While it has long been hypothesised that such switching is triggered by external cues, the identity of these cues has remained elusive. Here, we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of these rare cells showed flattened, elliptical nuclei suggestive of mechanical confinement by nearby adjacent tissue. Spatial and single-cell transcriptomics demonstrated that the interface cells adopted a gene program of neuronal invasion, including acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism for phenotype switching in melanoma.

2024-01-24 | GSE253802 | GEO

Mechanical confinement governs phenotypic plasticity in melanoma [confined_RNAseq]

2024-01-24 | GSE253800 | GEO

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>

2020-06-29 | MTBLS1764 | MetaboLights

Reciprocal regulation of cardiac chromatin by the chromatin structural proteins HMGB and CTCF

Project description:Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications and other chromatin features at pathology-associated genes. It remains unknown the extent to which genome-wide chromatin reorganization also contributes to the pathologic gene expression. We examined the roles of two chromatin structural proteins, CTCF (CCCTC-binding factor) and HMGB2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling. Our data demonstrate a reciprocal relationship between HMGB2 and CTCF in controlling aspects of chromatin structure and gene expression. Both proteins regulate each otherâs expression as well as transcription in cardiac myocytes: however, only HMGB2 does so in a manner that involves global reprogramming of chromatin accessibility. We demonstrate that the actions of HMGB2 on local chromatin accessibility are conserved across genomic loci, whereas the effects on transcription are loci-dependent and emerge in concert with histone modification and other chromatin features. Lastly, while both proteins share gene targets, HMGB2 and CTCF neither bind these genes simultaneously nor do they physically co-localize in myocyte nuclei. Our study uncovers a previously unknown relationship between these two ubiquitous chromatin proteins and provides a mechanistic explanation for how HMGB2 regulates gene expression and cellular phenotype. Furthermore, we demonstrate direct evidence for hierarchical remodeling of chromatin on a genome-wide scale in the setting of cardiac disease. Examination of a chromatin structural protein, HMGB2 in basal and agonist-treated cells.

2016-06-15 | E-GEOD-80453 | biostudies-arrayexpress

Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ and Wnt/β-catenin signaling in melanoma phenotype switching

Project description:In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFb/SMAD, Hippo/YAP/TAZ and Wnt/b-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFb/SMAD, YAP/TAZ and b-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of b-catenin, with YAP/TAZ governing an essential sub-program of TGFb-induced phenotype switching. Wnt/b-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ-induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

2021-11-11 | GSE188463 | GEO

Expression profiling of budding cells in colorectal cancer suggests an EMT-like phenotype and molecular subtype switching

Project description:Tumour buds undergo phenotype switching while detaching from the main tumour, as they acquire more migratory characteristics and tend to stop proliferating. Simultaneously, an EMT-like signature is observed in the tumour buds under the form of active WNT, TGF and receptor tyrosine kinase signalling. In addition, FOXA2 and RUNX2 well known transcription factors in other cancer types were also differentially expressed in the buds compared to the main tumour mass, hinting at the potential role in tumour budding and initiation of metastasis in colorectal cancer.

2017-02-04 | E-MTAB-4065 | biostudies-arrayexpress

Identification of gene expression signature for cigarette smoke exposure response--from man to mouse.

Project description:Gene expression signatures help to provide a global and robust view of biological processes in normal and pathological situations. Additionally, such signatures can be used in toxicology to assess both the level and impact of toxicant exposure, which is in line with the 21st century vision of toxicology. An 11 gene signature extracter by Martin et al. assist us in the evaluation of the reduction in exposure response in subjects enrolled in PMI clinical trials for THS 2.2 and THS 2.2 menthol assessment. The signature was applied to gene expression profiles from blood after 5-day cessation confinement studies, which showed a consistent decrease of the signature scores. Similarly, upon switching to THS2.2 for 5 days, a significant decrease in the signature score was consistently observed. Finally, in a study where a 5-day confinement period was followed by an 85-day ambulatory period, a similar decrease was observed for both cessation and switching to mentholated THS2.2.

2017-08-05 | E-MTAB-5333 | biostudies-arrayexpress

Mechanical Confinement Promotes Heat Resistance of Hepatocellular Carcinoma via SP1/IL4I1/AHR Axis

Project description:Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.

2023-06-25 | GSE235351 | GEO

The Escherichia coli nucleoid is shaped around replication and transcription [GCC]

Project description:The Escherichia coli nucleoid is confined within a rod shaped cell many times smaller than the outstretched chromosome. While extensive compaction is necessary for this process, the chromosome must at the same time remain accessible to essential cellular processes such as replication and transcription. Currently, the individual contributions of cellular confinement, chromosome topology, replication and transcription on nucleoid organization are not well understood. Here we synchronize E. coli cells in stationary phase, where replication has ceased, each cell contains only one copy of the chromosome, and transcription is minimal. We then release the cells and capture chromosome contacts and transcription immediately following release and through-out one cell cycle. Polymer models of confined and topologically constrained circular polymers revealed that cellular confinement and topology do not contribute extensively to the organization of the E. coli nucleoid. Rather, local nucleoid structure is established concurrent with replication, and higher order organization is formed by the replication dependant clustering of linearly distant SeqA bound sites and cell cycle specific gene transcription.

2017-12-25 | GSE87117 | GEO

The Escherichia coli nucleoid is shaped around replication and transcription [RNA-Seq]

2017-12-25 | GSE87071 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data