Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces

Liang, Cheng; Huang, Miao; Li, Tianqi; Li, Lü; Sussman, Hayley; Dai, Yanjun; Siemann, Dietmar W.; Xie, Mingyi; Tang, Xin

doi:10.1039/d1sm01618k

Cited by 15 publications

(10 citation statements)

References 411 publications

(793 reference statements)

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“…These inhibitors not only suppressed F-actin accumulation but also inhibited the transition, indicating the critical role of F-actin polymerization. In addition, inhibiting the EGFR-PI3K-Akt and calcium pathways, which are known regulators of F-actin dynamics [41][42][43][44][45] , also halted both F-actin accumulation and the transition (Fig. 2a, 3a, 4g and Supplementary Fig.…”

Section: Actin Bracket Formation Establishes Elastoplastic Transition...mentioning

confidence: 99%

Epithelial Folding Irreversibility is Controlled by Elastoplastic Transition via Mechanosensitive Actin Bracket Formation

Teranishi,

Mori,

Ichiki

et al. 2023

Preprint

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During morphogenesis, epithelial sheets fold sequentially to make up three-dimensional organ structures. The resulting fold is irreversible, thereby allowing morphogenesis to proceed unidirectionally. However, how the irreversibility of folding is established remains unclear. We report a novel mechanical property of epithelia that is responsible for folding irreversibility. In ex vivoandin vitrocultures, epithelia exhibit an elastic response and restore their original shapes when folding is induced by short-term mechanical indentation. In contrast, long-term indentation induces a plastic response, resulting in irreversible deformation. Remarkably, the transition from an elastic to a plastic response occurs in a switch-like manner with a critical duration. This transition is established by the accumulation of F-actin into a bracket-like structure across the fold, with the critical duration determined and tunable by the actin polymerization rate. Bracket formation and the resulting transition require two mechanosensing pathways: TRPC3/6-mediated calcium influx and ligand-independent epidermal growth factor receptor (EGFR) activation. While each pathway is independently triggered by deformation, calcium influx specifically occurs at the fold under EGFR activation. These results demonstrated that cells control epithelial folding irreversibility by detecting the temporal characteristics of deformation and adaptively switching between elastic and plastic responses. This finding, thus, resolves a long-standing question concerning the directionality of morphogenesis.

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Section: Actin Bracket Formation Establishes Elastoplastic Transition...mentioning

confidence: 99%

Epithelial Folding Irreversibility is Controlled by Elastoplastic Transition via Mechanosensitive Actin Bracket Formation

Teranishi,

Mori,

Ichiki

et al. 2023

Preprint

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“…Such scaffolds are designed and utilised to serve as a structural template that guides cells to autonomously form the types of hierarchical structures found in vivo [5][6][7]. Recent studies in bioengineering and mechanobiology have clarified that intrinsic cellular force and its interaction with geometrical cues from the surrounding environment have a crucial impact on cellular behaviour [8][9][10][11][12][13]; the influence of such forces is especially manifested in mechanical events such as collective cellular migration [14][15][16] and alignment [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Such scaffolds are designed and utilised to serve as a structural template that guides cells to autonomously form the types of hierarchical structures found in vivo [5–7]. Recent studies in bioengineering and mechanobiology have clarified that intrinsic cellular force and its interaction with geometrical cues from the surrounding environment have a crucial impact on cellular behaviour [8–13]; the influence of such forces is especially manifested in mechanical events such as collective cellular migration [14–16] and alignment [17–19]. These studies highlight the importance of a rational geometrical design of cell-culture scaffolds that correctly direct cellular behaviour based upon quantitative prediction, to construct a tissue with the desired structure and biological properties in vitro .…”

Section: Introductionmentioning

confidence: 99%

Multicellular dynamics on structured surfaces: Stress concentration is a key to controlling complex microtissue morphology on engineered scaffolds

Matsuzawa

Matsuo

Fukamachi

et al. 2023

Preprint

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Tissue engineers have utilized a variety of three-dimensional (3D) scaffolds for controlling multicellular dynamics and the resulting tissue microstructures. In particular, cutting-edge microfabrication technologies, such as 3D bioprinting, provide increasingly complex structures. However, unpredictable microtissue detachment from scaffolds, which ruins desired tissue structures, is becoming an evident problem. To overcome this issue, we elucidated the mechanism underlying microtissue detachment by combining a novel computational simulation method with quantitative tissue-culture experiments. We first quantified the stochastic processes of microtissue detachment shown by vascular smooth muscle cells on model curved scaffolds and found that microtissue morphologies vary drastically depending on cell contractility, substrate curvature, and cell-substrate adhesion strength. To explore this mechanism, we developed a new particle-based model that explicitly describes stochastic processes of multicellular dynamics, such as adhesion, rupture, and large deformation of microtissues on arbitrarily shaped 3D scaffolds. Computational simulations using the developed model successfully reproduced characteristic detachment processes observed in experiments. Crucially, simulations revealed that cellular contractility- induced stress is locally concentrated at the cell-substrate interface, subsequently inducing a catastrophic process of microtissue detachment, which can be suppressed by modulating cell contractility, substrate curvature, and cell-substrate adhesion. These results show that the developed computational method is useful for predicting engineered tissue dynamics as a platform for prediction-guided scaffold design.

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“…The crosstalk between mitochondria and endoplasmic reticulum (ER) through ITPRs, leading to calcium flux, has been identified as a crucial factor in determining senescence 31 and apoptosis 32 -two important targets in cancer. Some mechanical cues, such as flow, stretching, and substrate stiffness, can regulate calcium signaling to dictate cell functions and cancer progression [33][34][35][36] . Intracellular calcium concentration has also been related to cell volume 37,38 .…”

Section: Introductionmentioning

confidence: 99%

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

Gong,

Ogino,

Leite

et al. 2023

Preprint

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Liver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and β-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells.Significance statementCompression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.

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Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces

Abstract: An increasing number of studies have demonstrated the significant roles of the interplay between microenvironmental mechanics in tissues and biochemical-genetic activities in resident tumor cells at different stages of tumor...

Cited by 15 publications

References 411 publications

Epithelial Folding Irreversibility is Controlled by Elastoplastic Transition via Mechanosensitive Actin Bracket Formation

Epithelial Folding Irreversibility is Controlled by Elastoplastic Transition via Mechanosensitive Actin Bracket Formation

Multicellular dynamics on structured surfaces: Stress concentration is a key to controlling complex microtissue morphology on engineered scaffolds

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

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