Membrane ruffling is a mechanosensor of extracellular fluid viscosity

Pittman, Matthew; Iu, Ernest; Li, Keva; Wang, Mingjiu; Chen, Junjie; Taneja, Nilay; Jo, Myung Hyun; Park, Seungman; Jung, Wei‐Hung; Liang, Le; Barman, Ishan; Ha, Taekjip; Gaitanaros, Stavros; Liu, Jian; Burnette, Dylan T.; Plotnikov, Sergey V.; Chen, Yun

doi:10.1038/s41567-022-01676-y

Cited by 37 publications

(26 citation statements)

References 64 publications

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“…Elevated degradation of extracellular matrix at tumour sites also exacerbates macromolecular crowding 12 , which can further increase the viscosity of the interstitial fluid 13 . Notably, the physiological viscosity of whole blood varies between 4 and 6 cP, and can exceed 8 cP during pathological abnormalities 14 .Previous research has shown that supraphysiological viscosities (≥40 cP) increase the motility of carcinoma and normal cells on twodimensional (2D) surfaces 15,16 . This is rather counterintuitive, as viscosity slows down the motion of particles within fluids.…”

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confidence: 99%

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Extracellular fluid viscosity enhances cell migration and cancer dissemination

Bera

Kiepas

Godet

et al. 2022

Nature

119

104

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Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.

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confidence: 99%

“…Previous research has shown that supraphysiological viscosities (≥40 cP) increase the motility of carcinoma and normal cells on twodimensional (2D) surfaces 15,16 . This is rather counterintuitive, as viscosity slows down the motion of particles within fluids.…”

mentioning

confidence: 99%

Extracellular fluid viscosity enhances cell migration and cancer dissemination

Bera

Kiepas

Godet

et al. 2022

Nature

119

104

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“…First, important trafficking pathways between the endoplasmic reticulum rely on the formation of highly curved vesicles, and regulation of extramembrane crowding may be one mechanism through which vesicles alter morphology for vital processes including endocytosis and vesicle budding [62][63][64] . More generally, crowding-induced changes to local membrane curvature could also play a role in the shaping of organelles, and the triggering of adaptive cellular responses such as gene expression 65 . Second, our measurements indicate that extramembrane crowding leads to variations in the lipid packing density which does not always guarantee stability 66 .…”

Section: Discussionmentioning

confidence: 99%

Crowding induced morphological changes in synthetic lipid vesicles determined using smFRET

Quinn

Shepherd

Dresser

et al. 2022

Preprint

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Synthetic lipid vesicles are valuable mesoscale molecular confinement vessels for studying membrane mechanics and lipid-protein interactions, and they have found vast utility among bio-inspired technologies including drug delivery vehicles. Having a diameter of a few tens to hundreds of nanometers enables such complex processes to be studied at the level of a handful of molecules, conferring benefits in exploring molecular heterogeneity under near-physiological conditions. Vesicle morphology can be modified by changing the mixture of lipids used in creating them, fusing and lysing vesicles using proteins and detergents, or modifying the pH, temperature and ionic strength of the surrounding buffer, enabling the effects of membrane curvature on these processes to be explored. The requirements for experimental control have meant that most vesicle studies are performed under dilute solution conditions in vitro. The use of vesicles in crowded intracellular environments, known to influence the activities of many cellular processes, is limited by our knowledge of how molecular crowders affect vesicle morphology. To tackle this limitation, we used fluorescence spectroscopy, picosecond time correlated single photon counting and single-vesicle imaging to explore the influence of molecular crowding on the structure of freely-diffusing and surface-tethered vesicles fluorescently labelled with DiI and DiD. By quantifying single-molecule Förster resonance energy transfer (smFRET) between the probes, we determined the dependence on vesicle morphology from crowding using the molecular weight crowders sorbitol PEG400, Ficoll400 and PEG8000, identifying a common theme that both low and high molecular weight crowders trigger structural rearrangements of the vesicle that we assign to compaction. A particularly striking observation is that the low molecular weight crowder sorbitol results in irreversible changes to the smFRET efficiency attributed to permanent compaction, whereas the influence of the higher molecular weight crowders was found to be reversible. The effect of crowding perturbation on the architecture of such a reduced system not only emphasizes the power of single-vesicle approaches to probe complex biology, but also illustrates the potential to controllably alter the vesicle volume and radius of curvature for several biotechnological applications.

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“…For example, factors such as extracellular fluid viscosity, osmotic pressure, hydrostatic pressure, and compression can also alter the course of angiogenesis, but the detailed molecular mechanisms beyond such alterations are yet to be determined ( Park et al, 2020 ). Recent evidence has shown that elevated extracellular viscosity enhances cell motility ( Pittman et al, 2022 ), which may contribute to angiogenesis in regions of higher blood viscosity like the tumor microenvironment. Tissue engineered-based in vitro models capable of multiplexing are highly desirable so that multiple mechanical factors can be applied at varying quantities simultaneously.…”

Section: Future Directionsmentioning

confidence: 99%

Mechanical regulation of signal transduction in angiogenesis

Flournoy

Ashkanani

Chen

2022

Front. Cell Dev. Biol.

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Biophysical and biochemical cues work in concert to regulate angiogenesis. These cues guide angiogenesis during development and wound healing. Abnormal cues contribute to pathological angiogenesis during tumor progression. In this review, we summarize the known signaling pathways involved in mechanotransduction important to angiogenesis. We discuss how variation in the mechanical microenvironment, in terms of stiffness, ligand availability, and topography, can modulate the angiogenesis process. We also present an integrated view on how mechanical perturbations, such as stretching and fluid shearing, alter angiogenesis-related signal transduction acutely, leading to downstream gene expression. Tissue engineering-based approaches to study angiogenesis are reviewed too. Future directions to aid the efforts in unveiling the comprehensive picture of angiogenesis are proposed.

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Membrane ruffling is a mechanosensor of extracellular fluid viscosity

Cited by 37 publications

References 64 publications

Extracellular fluid viscosity enhances cell migration and cancer dissemination

Extracellular fluid viscosity enhances cell migration and cancer dissemination

Crowding induced morphological changes in synthetic lipid vesicles determined using smFRET

Mechanical regulation of signal transduction in angiogenesis

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