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Effect of long-term strong confinement on gene expression of HeLa Kyoto cells

ABSTRACT: Physical microenvironment confinement is a hallmark of the tumor landscape, yet the long-term impact of such mechanical constraints on cell fate remains elusive. While the mesenchymal–amoeboid transition (MAT) is known to enhance migratory capacity and therapy resistance, the regulatory mechanisms governing cell state adaptation under sustained physical pressure are not fully understood. In this study, we performed RNA-seq analysis on cancer cells subjected to prolonged physical space confinement to investigate the resulting transcriptional landscape. Our data reveal that sustained confinement serves as a potent mechanical cue that triggers a distinct migration mode conversion. Notably, we identify the necroptosis-related protein MLKL as a critical transcriptional target induced by prolonged confinement. These findings provide a novel link between mechanical stress, the MAT process, and potential alterations in cell fate.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328527 | GEO | 2026/09/06

REPOSITORIES: GEO

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Long-term confinement triggers RIPK3-independent necroptosis in amoeboid cancer cells to shape tumor evolution

Project description:The mesenchymal–amoeboid transition (MAT) confers enhanced migratory capacity and therapy resistance to cancer cells. To disseminate, MAT cancer cells squeeze through compacted intra-tumor spaces, breach matrix barriers, and infiltrate into the vasculature—a journey defined by sustained mechanical pressure. Yet how prolonged MAT under such pressure influences cell fate remains poorly understood. Here, we introduce the concept of “Long-term MAT” (L-MAT)—referring to cells with sustained MAT status under pressure—and demonstrate that L-MAT in non-adhesive three-dimensional microenvironments triggers a previously unrecognized RIPK3-independent necroptotic pathway. Mechanistically, the PIEZO1-STAT1 axis mediates transcriptional upregulation of MLKL, and elevated MLKL accumulates on the membrane even without detectable RIPK3 expression, driving necroptosis in cells traditionally considered necroptosis-resistant in 2D petri dish. Following MLKL activation, L-MAT cells exhibit progressive migration restriction prior to membrane rupture. Notably, MLKL-knockout cells bypass this checkpoint, retain motility, and persist as surviving clones. Spatial transcriptomic analysis of patient tumors reveals that MLKL expression correlates with local PIEZO1 activation and immunogenicity in less aggressive regions, whereas malignant and metastatic clones exhibit reduced MLKL levels. Our findings establish MLKL as a conditional tumor checkpoint that governs L-MAT cell fate, functioning as an intrinsic barrier against invasive amoeboid cancer cells independent of canonical death-receptor signaling. Counterintuitively, this selective pressure drives tumor evolution by enriching for necroptosis-resistant, aggressive clones. These results uncover an evolutionary bottleneck in cancer progression and identify the PIEZO1-STAT1-MLKL axis as a therapeutic target.

2026-09-05 | GSE328536 | GEO

DNA nanomachines reveal an adaptive energy mode in confinement-induced amoeboid migration powered by polarized mitochondrial distribution

Project description:<p>Energy metabolism is highly interdependent with adaptive cell migration <em>in vivo</em>. Mechanical confinement is a critical physical cue that induces switchable migration modes of the mesenchymal-to-amoeboid transition (MAT). However, the energy states in distinct migration modes, especially amoeboid-like stable bleb (A2) movement, remain unclear. In this report, we developed multivalent DNA framework-based nanomachines to explore strategical mitochondrial trafficking and differential ATP levels during cell migration in mechanically heterogeneous microenvironments. Through single-particle tracking and metabolomic analysis, we revealed that fast A2-moving cells driven by biomimetic confinement recruited back-end positioning of mitochondria for powering highly polarized cytoskeletal networks, preferentially adopting an energy-saving mode compared with a mesenchymal mode of cell migration. We present a versatile DNA nanotool for cellular energy exploration and highlight that adaptive energy strategies coordinately support switchable migration modes for facilitating efficient metastatic escape, offering a new perspective for therapeutic interventions in cancer metastasis.</p>

2024-03-25 | MTBLS9657 | MetaboLights

Mitochondrial fuels ATP in the nucleus to prevent cell cycle arrest during mechanical confinement

Project description:Abstract The physical microenvironment regulates cell behaviour during tissue development and disease. Whether mechanical stress and physical space constraints reshape the subcellular localization of organelles and proteins resulting in functional adaptations is, however, unknown. Here, we performed proteomic analysis to understand how proteins reorganise between the nucleus and the cytoplasm when cancer cells are acutely confined. We discovered that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that upon confinement mitochondria, in an actin-dependent manner, are trapped within an ER-based net that indents the nucleus. At the functional level, the close proximity of mitochondria and the nucleus results in a nuclear ATP surge, which is reverted by inhibiting ATP mitochondrial export or actin polymerisation. Pharmacological prevention of this confinement-induced nuclear ATP surge impedes cell proliferation through cell cycle defects. Taken together, our data indicates that the physical association between the nucleus and mitochondria is a functional requirement for cell cycle completion after acute mechanical stress.

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Fine control of nuclear confinement identifies a threshold deformation leading to lamina rupture and induction of specific genes

Project description:The quest to understand how the mechanical and geometrical environment of cells impacts their behaviour and fate has been a major force driving the recent development of new technologies in cell biology research. Despite rapid advances in this field, many challenges remain in order to bridge the gap between the classical and simple cell culture plate and the biological reality of actual tissue. In tissues, cells have their physical space constrained by neighbouring cells and the extracellular matrix. Here, we propose a simple and versatile device to precisely and dynamically control this confinement parameter in cultured cells. We show that there is a precise threshold deformation above which the nuclear lamina breaks and reconstructs, whereas nuclear volume changes. We also show that different nuclear deformations correlate with the expression of specific sets of genes, including nuclear factors and classical mechano-transduction pathways. This versatile device thus enables the precise control of cell and nuclear deformation by confinement and the correlative study of the associated molecular events.

2018-10-31 | E-MTAB-7339 | biostudies-arrayexpress

Mitochondria-derived nuclear ATP surge protects against mechanical confinement-induced proliferation defects

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2025-06-10 | GSE248846 | GEO

Mechanical confinement governs phenotypic plasticity in melanoma

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 tumor cells at the interface between the tumor and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei suggestive of mechanical confinement by 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 favor the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumor cells are less proliferative but more drug resistant. Our results implicate the mechanical microenvironment as a mechanism driving phenotype switching in melanoma.

2025-08-26 | PXD060265 | Pride

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Project description:Mechanical confinement prevents ectopic platelet release

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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

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 [HMGB2OE_RNAseq]

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.

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