Biology subjects

Venturini, V.

Publications and source records attributed to Venturini, V..

4 recordsLinked to original sources

bioRxiv2024

Cell-matrix force transmission regulates the loss of naïve pluripotency in mouse embryonic stem cells.

The first step in the differentiation of mouse embryonic stem cells (mESCs) is the loss of naive pluripotency. This step involves a major reshaping of cells from a rounded to a spread, adhesive phenotype. Whereas such reshaping is typically associated with increased force transmission to the extracellular matrix (ECM), the magnitude and role of cell-matrix forces in the loss of naive pluripotency is unknown. Here, we show that cell-matrix forces increase during, and are required for, the loss of naive pluripotency in mESCs. Using traction force microscopy, we show that mESCs progressively increase cell-traction forces and mechanotransduction markers as naive pluripotency dissolves. Modulation of force transmission through myosin inhibition, substrate stiffness, or spatial differences within mESC colonies regulates the process. Increased force is triggered by GSK3-mediated signalling, and the effect of force is regulated in part by its transmission to the cell nucleus. Our work unveils a major role of cell-ECM forces in pluripotency dissolution, adding an important aspect to the interplay between biochemical and biophysical cues that drive this process.

developmental biology↗

bioRxiv2023

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

The physical microenvironment regulates cell behaviour. However, whether physical confinement rewires the subcellular localisation of organelles and affect metabolism is unknown. Proteomics analysis revealed that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery. This nuclear-mitochondrial proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the mitochondrial proximity results in a nuclear ATP surge, which can be reverted by the pharmacological inhibition of mitochondrial ATP production or via actin depolymerisation. Inhibition of the confinement-derived nuclear ATP surge reveals long-term effects on cell fitness which arise from alterations of chromatin states, delayed DNA damage repair, and impaired cell cycle progression. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell cycle progression by allowing chromatin state transitions.

cell biology↗

bioRxiv2023

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

Colorectal cancer 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 unknown. Using CRC patient derived organoids (PDOs), we found 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 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.

cancer biology↗

bioRxiv2019

The nucleus measures shape deformation for cellular proprioception and regulates adaptive morphodynamics

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 their local environment remains largely unknown. Here we show that the nucleus, the biggest cellular organelle, functions as a non-dissipative cellular shape deformation gauge that enables cells to continuously measure shape variations on the time scale of seconds. Inner nuclear membrane unfolding together with the relative spatial intracellular positioning of the nucleus provides physical information on the amplitude and type of cellular shape deformation. This adaptively activates a calcium-dependent mechano-transduction pathway, controlling the level of 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 behaviour to their microenvironment. One Sentence SummaryThe nucleus functions as an active deformation sensor that enables cells to adapt their behavior to the tissue microenvironment.

cell biology↗