Inhomogeneous mechanotransduction defines the spatial pattern of apoptosis-induced compensatory proliferation

Kawaue, Takumi; Yow, Ivan; Pan, Yongdong; Le, Anh Phuong; Lou, Yuting; Loberas, Mavis; Shagirov, Murat; Teng, Xiang; Prost, Jacques; Hiraiwa, Tetsuya; Ladoux, Benoît; Toyama, Yusuke

doi:10.1016/j.devcel.2023.01.005

Cited by 12 publications

(6 citation statements)

References 48 publications

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“…[107] PDMS gel was utilized to create a soft 15 kPa TFM substrate by preparing a mixture of CY52-276A and CY52-276B components (Dow Corning) at 1:1 ratio, as described by earlier works. [108,109] Approximately 40 μL volume of PDMS mixture was pipetted on each glass bottom dish (IBIDI) and spincoated for 1 min at 1000 rpm before curing in 80 °C oven for 2 h. Next, PDMS surface was silanized with 5% 3-Aminopropyl)trimethoxysilane (Sigma A3648) diluted with absolute ethanol for 15 min before washing off with absolute ethanol and dried inside the 80 °C oven for 1 h. Fluorescent nanobead solution was prepared at 1:500 ratio with distilled water and carboxylate-modified microspheres of diameter 0.2 μm, dark red fluorescent (660/680 nm), 2% solids (Invitrogen). Bead solution was then poured onto the dish and incubated for 15 min before aspiration and further dried inside the 80 °C oven for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Hiltonol, a dsRNA Mimic, Promotes NK Cell Anticancer Cytotoxicity Through TAZ Cytoplasmic Sequestration

Wong

Xia

Shao

et al. 2023

Advanced Therapeutics

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The evolutionarily conserved YAP/TAZ mechanoresponsive transcription cofactors regulate development and tumorigenesis. Here, it is shown for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The synthetic double-stranded RNA, hiltonol, is able to trigger cytoplasmic compartmentalization of TAZ, which increases NK cytotoxicity. Mechanistically, a low dose of hiltonol enhances the actin-based intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation-dependent ROS production. Importantly, it is showed that the dissociation of LATS1 from actin upon activation of contractility is associated with TAZ cytoplasmic localization. Functionally, hiltonol also reduces the NK cell surface inhibitory receptors, e.g., KIR3DL1, through c-Myc inhibition. Direct inhibition of c-Myc promotes NK cytotoxicity against K562 lymphoblast. The findings are corroborated by coculturing hiltonol-pretreated NK cells with breast and lung cancer cells, and increased NK-mediated cancer killing is demonstrated, which conceivably occurs via compartmentalization of TAZ to the cytoplasm which facilitates NK cytotoxicity. The findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which can involve a cocktail of low dose hiltonol and c-Myc inhibitor.

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Section: Methodsmentioning

confidence: 99%

Hiltonol, a dsRNA Mimic, Promotes NK Cell Anticancer Cytotoxicity Through TAZ Cytoplasmic Sequestration

Wong

Xia

Shao

et al. 2023

Advanced Therapeutics

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“…For downstream analysis requiring quantification for each cell, a code was customised to import ImageJ ROIs into MATLAB to calculate the parameters for each ROI. Radial traction stress is analysed as previously described, with the middle of initially spreading cells or fracture site being the point of reference 56 . Statistical analysis was performed using one-way ANOVA in GraphPad Prism.…”

Section: Methodsmentioning

confidence: 99%

“…Radial traction stress is analyzed as previously described with the middle of initially spreading cells or fracture site being the point of reference. 56 . Statistical analysis was performed using one-way ANOVA in GraphPad Prism.…”

Section: Methodsmentioning

confidence: 99%

A morphogenic cascade emerges from the co-evolution of spheroid fluidization and fracturing of multicellular barriers

Wu,

Ho,

Sun

et al. 2023

Preprint

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Cell collectives can undergo solid to fluid states transition and break apart during development and disease. How these processes coordinate collective cell invasion of a tissue barrier, as well as the underlying biological and physical principles, remains unclear. Using a three-dimensional model system of cancer spheroids invading the mesothelium, we find that the mesothelial cell-cell contacts undergo tensile fracturing as the spheroid invades. This tensile fracture is triggered by mesothelial cell apical constriction, a consequence of intercellular integrin complex engagement between the spheroid leader cell and the mesothelial cell. Concurrently, persistent directed migration of spheroid cells propagate the mesothelial fracture. In response, the deformed mesothelium exerts resisting forces on the fluidizing spheroid, leading to a crowding effect and contact inhibition of the fluidizing spheroid. We have uncovered a morphogenic cascade, revealing that the invasion of cells into adjacent cellular and extracellular matrix-rich microenvironment emerges from the co-evolution of spheroid fluidization and mesothelium fracture triggered by intercellular integrin complex engagement.

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“…Although only a limited number of neighboring cells must divide to compensate for cell loss, the mechanisms that select cells for division have not been fully elucidated. A recent study using an MDCK monolayer cell culture system revealed that the inhomogeneous activity of YAP-mediated mechanotransduction in neighboring cells determines cell division for compensatory proliferation [ 65 ]. This inhomogeneity in YAP activity arises from the nonuniform distribution of nuclear size and the mechanical force exerted on neighboring cells.…”

Section: Main Textmentioning

confidence: 99%

Hippo pathway in cell–cell communication: emerging roles in development and regeneration

Nita,

Moroishi

2024

Inflamm Regener

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The Hippo pathway is a central regulator of tissue growth that has been widely studied in mammalian organ development, regeneration, and cancer biology. Although previous studies have convincingly revealed its cell-autonomous functions in controlling cell fate, such as cell proliferation, survival, and differentiation, accumulating evidence in recent years has revealed its non-cell-autonomous functions. This pathway regulates cell–cell communication through direct interactions, soluble factors, extracellular vesicles, and the extracellular matrix, providing a range of options for controlling diverse biological processes. Consequently, the Hippo pathway not only dictates the fate of individual cells but also triggers multicellular responses involving both tissue-resident cells and infiltrating immune cells. Here, we have highlighted the recent understanding of the molecular mechanisms by which the Hippo pathway controls cell–cell communication and discuss its importance in tissue homeostasis, especially in development and regeneration.

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Inhomogeneous mechanotransduction defines the spatial pattern of apoptosis-induced compensatory proliferation

Cited by 12 publications

References 48 publications

Hiltonol, a dsRNA Mimic, Promotes NK Cell Anticancer Cytotoxicity Through TAZ Cytoplasmic Sequestration

Hiltonol, a dsRNA Mimic, Promotes NK Cell Anticancer Cytotoxicity Through TAZ Cytoplasmic Sequestration

A morphogenic cascade emerges from the co-evolution of spheroid fluidization and fracturing of multicellular barriers

Hippo pathway in cell–cell communication: emerging roles in development and regeneration

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