Mechanical confinement governs phenotypic plasticity in melanoma

Hunter, Miranda V.; Montal, Emily; Ma, Yilun; Moncada, Reuben; Yanai, Itai; Koche, Richard P.; White, Richard M.

doi:10.1101/2024.01.30.577120

Cited by 4 publications

(1 citation statement)

References 105 publications

(139 reference statements)

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“…While jamming-unjamming transitions have become a well-established framework to explain cancer invasion, the underlying biological mechanisms are poorly understood. Recent studies have revealed possible mechanisms that impact plasticity pathways such as the ERK1/2 pathway, which triggers cell motility and results in collective invasive strands 16 , and a mechanosensitive pathway, in which cellular confinement directly causes deformations of the cell nuclei accompanied by chromatin remodelling 69 . Here we showed evidence that EMT is also a mechanism involved in 3D unjamming transitions by regulating cell-matrix interplay.…”

Section: Discussionmentioning

confidence: 99%

EMT-dependent cell-matrix interactions are linked to unjamming transitions in cancer spheroid invasion

van der Net,

Rahman,

Bordoloi

et al. 2024

Preprint

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The plasticity of cancer cells allows them to switch between different migration modes, promoting their invasion into the extracellular matrix (ECM) and hence increasing the risks of metastasis. Epithelial-to-mesenchymal transitions (EMT) and unjamming transitions provide two distinct pathways for cancer cells to become invasive, but it is still unclear to what extent these pathways are connected. Here we addressed this question by performing 3D spheroid invasion assays of lung adenocarcinoma (A549, epithelial) and melanoma (MV3, mesenchymal-like) cancer cell lines in collagen-based hydrogels, where we varied both the invasive character of the cells (using Transforming Growth Factor (TGF)-$\beta$ to promote EMT and matrix metalloprotease (MMP) inhibition to block cell-mediated matrix degradation) and the porosity of the matrix. Using a quantitative image analysis method to track spheroid invasion, we discovered that the onset time of invasion mostly depended on the matrix porosity and corresponded with vimentin levels, while the subsequent spheroid expansion rate mostly depended on metalloprotease MMP1 levels and thus cell-matrix interaction. Morphological analysis revealed that spheroids displayed solid-like (non-invasive) behavior in small-pore hydrogels and switched to fluid-like (strand-based) or gas-like (disseminating cells) phases in large-pore hydrogels and when cells were more mesenchymal-like. Our findings are consistent with unjamming transitions as a function of cell motility and matrix confinement predicted in recent models for cancer invasion, but show that cell motility and matrix confinement are coupled via EMT-dependent matrix degradation.

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Section: Discussionmentioning

confidence: 99%

EMT-dependent cell-matrix interactions are linked to unjamming transitions in cancer spheroid invasion

van der Net,

Rahman,

Bordoloi

et al. 2024

Preprint

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Evidence of Epigenetic Oncogenesis: A Turning Point in Cancer Research

Capp,

Aliaga,

Pancaldi

2024

BioEssays

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In cancer research, the term epigenetics was used in the 1970s in its modern sense encompassing non‐genetic events modifying the chromatin state, mainly to oppose the emerging oncogene paradigm. However, starting from the establishment of this prominent concept, the importance of these epigenetic phenomena in cancer rarely led to questioning the causal role of genetic alterations. Only in the last 10 years, the accumulation of problematic data, better experimental technologies, and some ambitious models pushed the idea that epigenetics could be at least as important as genetics in early oncogenesis. Until this year, a direct demonstration of epigenetic oncogenesis was still lacking. Now, Parreno, Cavalli and colleagues, using a refined experimental model in the fruit fly Drosophila melanogaster, enforced the initiation of tumors solely by imposing a transient loss of Polycomb repression, leading to a purely epigenetic oncogenesis phenomenon. Despite a few caveats that we discuss, this pioneering work represents a major breakpoint in cancer research. We are led to consider the theoretical and conceptual implications on oncogenesis and to search for links between this artificial experimental model and naturally occurring processes, while revisiting cancer theories that were previously proposed as alternatives to the oncogene‐centered paradigm.

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Global chromatin reorganization and regulation of genes with specific evolutionary ages during differentiation and cancer

Raynal,

Sengupta,

Plewczynski

et al. 2023

Preprint

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The availability of unprecedented datasets detailing the organization of chromatin across species, developmental stages, cell types and diseases invites an integrated analysis of genome organization in three dimensions and its biological significance.In this study we attempt to formalize a hypothesis according to which the topological properties of the chromatin network can impact phenotypes, such as plasticity and variability. Our observations lead us to reconsider the theory according to which cancer cells re-acquire pluripotency through a reactivation of early evolutionary programs characteristic of species lacking complex body plans or even multicellularity.Recent work investigating gene variability across tissues and individuals in multiple species has shown that promoter sequence characteristics can be predictive of gene expression variability. Exploiting this dataset and others, we show that genes with specific promoter features and associated similar values of expression variability tend to have specific epigenomic marks and form preferential interactions in 3D, as quantified by chromatin assortativity. We then investigate whether rearrangements of the 3D topology of the chromatin network in differentiation and oncogenesis can change these associations between gene regulation and evolutionary age. We observed that evolutionary older genes, also broadly corresponding to the least variable genes, are strongly clustered in the chromatin network.We characterize the topology of promoter-centered chromatin networks as well as assortativities of gene ages and expression variability in multiple datasets capturing topological changes in differentiation (embryonic stem cells, B cells) and find some of these changes to be reversed during oncogenesis.

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Mechanical confinement governs phenotypic plasticity in melanoma

Cited by 4 publications

References 105 publications

EMT-dependent cell-matrix interactions are linked to unjamming transitions in cancer spheroid invasion

EMT-dependent cell-matrix interactions are linked to unjamming transitions in cancer spheroid invasion

Evidence of Epigenetic Oncogenesis: A Turning Point in Cancer Research

Global chromatin reorganization and regulation of genes with specific evolutionary ages during differentiation and cancer

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