direct-force-measurements-subcellular-mechanics-confinement-using

Direct Force Measurements of Subcellular Mechanics in Confinement using Optical Tweezers

During the development of a multicellular organism, a single fertilized cell divides and gives rise to multiple tissues with diverse functions. Tissue ...

equibiaxial-stretching-device-for-high-magnification-live-cell

Equibiaxial Stretching Device for High Magnification Live-Cell Confocal Fluorescence Microscopy

Cells are continuously exposed to mechanical forces in physiological and pathological situations, including a variety of tensile and compressive stresses. ...

Institut de Ciències Fotòniques, ICFO

The Barcelona Institute of Science and Technology

Barcelona Institute of Science and Technology (BIST)

The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within tissues remains largely unknown. Here, using a zebrafish model, we show that the nucleus, the biggest cellular organelle, functions as an elastic deformation gauge that enables cells to measure cell shape deformations. Inner nuclear membrane unfolding upon nucleus stretching provides physical information on cellular shape changes and adaptively activates a calcium-dependent mechanotransduction pathway, controlling actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behavior to their microenvironment.

The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior.

Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.

Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells.

Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single adhesive cells, mechanotransduction involves the transmission of force from the extracellular matrix to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators, such as YAP (also known as YAP1). However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that NCT responds to mechanical forces but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks and to the inhibition of cell contractility. Furthermore, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast, YAP is sensitive to cell density, showing that the YAP response to cell-cell contacts is not via a mere mechanical effect of NCT. Our results demonstrate the generality of the mechanical regulation of NCT.

Nucleocytoplasmic transport senses mechanical forces independently of cell density in cell monolayers.

From border cell migration during Drosophila embryogenesis to solid stresses inside tumors, cells are often compressed during physiological and pathological processes, triggering major cell responses. Cell compression can be observed in vivo but also controlled in vitro through tools such as micro-channels or planar confinement assays. Such tools have recently become commercially available, allowing a broad research community to tackle the role of cell compression in a variety of contexts. This has led to the discovery of conserved compression-triggered migration modes, cell fate determinants and mechanosensitive pathways, among others. In this Review, we will first address the different ways in which cells can be compressed and their biological contexts. Then, we will discuss the distinct mechanosensing and mechanotransducing pathways that cells activate in response to compression. Finally, we will describe the different in vitro systems that have been engineered to compress cells.

ArticleTotal : 2	Year
Publication title Cited by 14	2021
Publication title Cited by 1	2025

Article	Year
The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science (New York, N.Y.)\| PubMed ID: 33060331	2020
Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells. Nature communications\| PubMed ID: 38637494	2024
Nucleocytoplasmic transport senses mechanical forces independently of cell density in cell monolayers. Journal of cell science\| PubMed ID: 39120491	2024
Cell compression - relevance, mechanotransduction mechanisms and tools. Journal of cell science\| PubMed ID: 40145202	2025

Valeria Venturini

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