Papers by Elisabeth Fischer-friedrich
bioRxiv (Cold Spring Harbor Laboratory), Feb 8, 2024
Life science alliance, May 17, 2024
Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, prot... more Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasisrelated cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.
New Journal of Physics, May 1, 2023
Developing tissues need to pattern themselves in space and time. A prevalent mechanism to achieve... more Developing tissues need to pattern themselves in space and time. A prevalent mechanism to achieve this are pulsatile active stresses generated by the actin cytoskeleton. Active gel theory is a powerful tool to model the dynamics of cytoskeletal pattern formation. In theoretical models, the influence of the viscoelastic nature of the actin cytoskeleton has so far only been investigated by the incorporation of one viscoelastic relaxation time scale. Here, using a minimal model of active gel theory, we show that distinct shear and areal relaxation times are sufficient to drive pulsatile dynamics in active surfaces with only a single molecular regulator.
Biophysical Journal, Sep 1, 2020
Mechanosensation of cells is an important prerequisite for cellular function, e.g., in the contex... more Mechanosensation of cells is an important prerequisite for cellular function, e.g., in the context of cell migration, tissue organization, and morphogenesis. An important mechanochemical transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers such as α-actinin-4 exhibit mechanosensitive properties in their binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a, to our knowledge, new technique that allows us to quantitatively characterize the dependence of cross-linking lifetime of actin cross-linkers on mechanical tension in the actin cortex of live cells. We use an approach that combines parallel plate confinement of round cells, fluorescence recovery after photobleaching, and a mathematical mean-field model of cross-linker binding. We apply our approach to the actin cross-linker α-actinin-4 and show that the cross-linking time of α-actinin-4 homodimers increases approximately twofold within the cellular range of cortical mechanical tension, rendering α-actinin-4 a catch bond in physiological tension ranges.
arXiv (Cornell University), May 12, 2023
The actin cortex is an active biopolymer network underneath the plasma membrane at the periphery ... more The actin cortex is an active biopolymer network underneath the plasma membrane at the periphery of mammalian cells. It is a major regulator of cell shape through the generation of active cortical tension. In addition, the cortex constitutes a mechanical shield that protects the cell during mechanical agitation. Cortical mechanics is tightly controlled by the presence of actin cross-linking proteins, that dynamically bind and unbind actin filaments. Cross-linker actin bonds are weak non-covalent bonds whose bond lifetime is likely affected by mechanical tension in the actin cortex making cortical composition inherently mechanosensitive. Here, we present a quantitative study of changes in cortex composition and turnover dynamics upon short-lived peaks in active and passive mechanical tension in mitotic HeLa cells. Our findings disclose a twofold mechanical reinforcement strategy of the cortex upon tension peaks entailing i) a direct catch-bond mechanosensitivity of cross-linkers filamin and α-actinin and ii) an indirect cortical mechanosensitivity that triggers actin cortex reinforcement via enhanced polymerization of actin. We thereby disclose a 'molecular safety belt' mechanism that protects the cortex from injury upon mechanical challenges.
New Journal of Physics, May 1, 2023
The cell cortex is an active viscoelastic self-deforming sheet at the periphery of animal cells. ... more The cell cortex is an active viscoelastic self-deforming sheet at the periphery of animal cells. It constricts animal cells during cell division. For some egg cells, the actomyosin cortex was shown to exhibit counter-rotating chiral flows along the axis of division. Such chiral surface flows were shown to contribute to spatial rearrangements and left-right symmetry breaking in developing organisms. In spite of this prospective biological importance, the effect of chiral forces on the flows and emergent shape dynamics of a deformable surface are completely unknown. To shed a first light on that matter, we present here a numerical study of an axisymmetric viscoelastic surface embedded in a viscous fluid. We impose a generic counter-rotating force field on this surface and study the resulting chiral flow field and shape dynamics for various surface mechanical parameters. Notably, we find that the building of a neck, as is observed during cell division, occurs if the surface contains a strong shear elastic component. Furthermore, we find that a large areal relaxation time results in flows towards the equator of the surface. These flows assist the transport of a surface concentration during the formation of a contractile ring. Accordingly, we show that chiral forces by themselves can drive pattern formation and stabilise contractile rings at the equator. These results provide first mechanistic evidence that chiral flows can play a significant role to orchestrate cell division.
The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, c... more The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, cancer cells were shown to change their actin cytoskeleton and their mechanical properties in correlation with different degrees of malignancy and metastatic potential. Epithelial-Mesenchymal transition (EMT) is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the frequency-dependent viscoelastic mechanics of the actin cortex is still lacking. In this work, we have used an established AFM-based method of cell confinement to quantify the rheology of the actin cortex of human breast, lung and prostate epithelial cells before and after EMT in a frequency range of 0.02 − 2 Hz. Interestingly, we find for all cell lines opposite EMT-induced changes in interphase and mitosis; while the actin cortex softens upon EMT in interphase, the cortex stiffens in mitosis. Our rheological data can be accounted for by a rheological model with a characteristic time scale of slowest relaxation. In conclusion, our study discloses a consistent rheological trend induced by EMT in human cells of diverse tissue origin reflecting major structural changes of the actin cytoskeleton upon EMT.
Advanced Science, Aug 9, 2020
To undergo mitosis successfully, most animal cells need to acquire a round shape to provide space... more To undergo mitosis successfully, most animal cells need to acquire a round shape to provide space for the mitotic spindle. This mitotic rounding relies on mechanical deformation of surrounding tissue and is driven by forces emanating from actomyosin contractility. Cancer cells are able to maintain successful mitosis in mechanically challenging environments such as the increasingly crowded environment of a growing tumor, thus, suggesting an enhanced ability of mitotic rounding in cancer. Here, it is shown that the epithelial–mesenchymal transition (EMT), a hallmark of cancer progression and metastasis, gives rise to cell‐mechanical changes in breast epithelial cells. These changes are opposite in interphase and mitosis and correspond to an enhanced mitotic rounding strength. Furthermore, it is shown that cell‐mechanical changes correlate with a strong EMT‐induced change in the activity of Rho GTPases RhoA and Rac1. Accordingly, it is found that Rac1 inhibition rescues the EMT‐induced cortex‐mechanical phenotype. The findings hint at a new role of EMT in successful mitotic rounding and division in mechanically confined environments such as a growing tumor.
Physical Biology, Oct 21, 2011
Bacterial cell division takes place in three phases: Z-ring formation at midcell, followed by div... more Bacterial cell division takes place in three phases: Z-ring formation at midcell, followed by divisome assembly and building of the septum per se. Using time-lapse microscopy of live bacteria and a high-precision cell edge detection method, we have previously found the true time for the onset of septation, τ(c), and the time between consecutive divisions, τ(g). Here, we combine the above method with measuring the dynamics of the FtsZ-GFP distribution in individual Escherichia coli cells to determine the Z-ring positioning time, τ(z). To analyze the FtsZ-GFP distribution along the cell, we used the integral fluorescence profile (IFP), which was obtained by integrating the fluorescence intensity across the cell width. We showed that the IFP may be approximated by an exponential peak and followed the peak evolution throughout the cell cycle, to find a quantitative criterion for the positioning of the Z-ring and hence the value of τ(z). We defined τ(z) as the transition from oscillatory to stable behavior of the mean IFP position. This criterion was corroborated by comparison of the experimental results to a theoretical model for the FtsZ dynamics, driven by Min oscillations. We found that τ(z) < τ(c) for all the cells that were analyzed. Moreover, our data suggested that τ(z) is independent of τ(c), τ(g) and the cell length at birth, L(0). These results are consistent with the current understanding of the Z-ring positioning and cell septation processes.
Physical Biology
Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological a... more Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological and pathological processes ranging from cancer over wound healing to embryogenesis. Changes in cell migration, cell morphology and cellular contractility were identified as hallmarks of EMT. These cellular properties are known to be tightly regulated by the actin cytoskeleton. EMT-induced changes of actin-cytoskeletal regulation were demonstrated by previous reports of changes of actin cortex mechanics in conjunction with modifications of cortex-associated f-actin and myosin. However, at the current state, the changes of upstream actomyosin signaling that lead to corresponding mechanical and compositional changes of the cortex are not well understood. In this work, we show in breast epithelial cancer cells MCF-7 that EMT results in characteristic changes of the cortical association of Rho-GTPases Rac1, RhoA and RhoC and downstream actin regulators cofilin, mDia1 and Arp2/3. In the light o...
arXiv (Cornell University), Feb 20, 2023
Developing tissues need to pattern themselves in space and time. A prevalent mechanism to achieve... more Developing tissues need to pattern themselves in space and time. A prevalent mechanism to achieve this are pulsatile active stresses generated by the actin cytoskeleton. Active gel theory is a powerful tool to model the dynamics of cytoskeletal pattern formation. In theoretical models, the influence of the viscoelastic nature of the actin cytoskeleton has so far only been investigated by the incorporation of one viscoelastic relaxation time scale. Here, using a minimal model of active gel theory with a single molecular regulator, we show that distinct shear and areal relaxation times are sufficient to drive pulsatile dynamics in active surfaces.
Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological a... more Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological and pathological processes ranging from cancer over wound healing to embryogenesis. Changes in cell migration, cell morphology and cellular contractility were identified as hallmarks of EMT. These cellular properties are known to be tightly regulated by the actin cytoskeleton. EMT-induced changes of actin-cytoskeletal regulation were demonstrated by previous reports of cell-cycle-dependent changes of actin cortex mechanics in conjunction with characteristic modifications of cortex-associated factin and myosin. However, at the current state, the changes of upstream actomyosin signalling that lead to corresponding mechanical and structural changes of the cortex are not well understood. In this work, we show in breast epithelial cancer cells MCF-7 that EMT results in characteristic changes of the cortical signalling of Rho-GTPases Rac1, RhoA and RhoC and downstream actin regulators cofilin, ...
Physical Biology, 2006
In the bacterium Escherichia coli, selection of the division site involves pole-to-pole oscillati... more In the bacterium Escherichia coli, selection of the division site involves pole-to-pole oscillations of the proteins MinD and MinE. Different oscillation mechanisms based on cooperative effects between Min-proteins and on the exchange of Min-proteins between the cytoplasm and the cytoplasmic membrane have been proposed. The parameters characterizing the dynamics of the Min-proteins in vivo are not known. It has therefore been difficult to compare the models quantitatively with experiments. Here, we present in vivo measurements of the mobility of MinD and MinE using fluorescence correlation spectroscopy. Two distinct timescales are clearly visible in the correlation curves. While the faster timescale can be attributed to cytoplasmic diffusion, the slower timescale could result from diffusion of membrane-bound proteins or from protein exchange between the cytoplasm and the membrane. We determine the diffusion constant of cytoplasmic MinD to be approximately 16µm 2 /s, while for MinE we find about 10µm 2 /s, independently of the processes responsible for the slower timescale. Implications of the measured values for the oscillation mechanism are discussed.
Cornell University - arXiv, Nov 14, 2022
During division in animal cells, the actomyosin cortex has been found to exhibit counter-rotating... more During division in animal cells, the actomyosin cortex has been found to exhibit counter-rotating cortical flows, also known as chiral flows, along the axis of division. Furthermore, such chiral surface flows were shown to influence cellular rearrangements and drive the left-right symmetry breaking in developing organisms. In spite of this prospective biological importance, at the current state, no numerical simulations have been done to study the influence of chiral flows on the cell cortex shape. To deepen the insight on that matter, we present here a numerical study of an axi-symmetric viscoelastic surface embedded in a viscous fluid. To investigate the influence of a chiral flow field on the surface shape and material transport, we impose a generic counter-rotating force field on this surface which induces a chiral flow field. Notably, we find that the building of a neck, as is observed during cell division, occurs if there is a strong shear elastic component. Furthermore we find that a large areal relaxation time results in flows towards the equator of the surface. These flows assist the transport of a surface concentration during the forming of a contractile ring. Accordingly, we show that chiral forces by themselves can drive pattern formation and stabilise contractile rings at the equator.
What is the Min System? Min proteins are a class of proteins that is widely conserved among bacte... more What is the Min System? Min proteins are a class of proteins that is widely conserved among bacteria. They are involved in locating the cell division machinery of the bacterium to the cell middle and form a part of the bacterial cytoskeleton. In the rod-shaped bacterium Escherichia coli, there are three Min proteins, namely MinC, MinD and MinE. These proteins form spatiotemporal patterns in the E. coli cell which are characterized by concentration maxima that oscillate from one cell pole to the other. Such Min oscillations prohibit the localization of the division plane to the cell poles and prevent in this way the formation of anucleate daughter cells - so-called mini cells. Our objective. There are strong indications that the pattern produced by the Min system in Escherichia coli is self-organized. In fact, MinD and MinE self-organize into traveling waves and spirals in vitro on a planar membrane. In this work, we want to understand by which mechanism the dynamic instability is ge...
Methods in molecular biology, 2022
The shaping of epithelial tissues into functional organs often depend on asymmetries in mechanica... more The shaping of epithelial tissues into functional organs often depend on asymmetries in mechanical tension present at the apical and basal sides of cells. Contraction of an actomyosin meshwork underlying the apical side of cells is known to generate apical tension. The basal side of cells is also associated with an actomyosin meshwork, but it is, in addition, connected to a specialized extracellular matrix, the basement membrane. However, how basal tension is generated, and the role of the basement membrane in this process, are not well understood. Here, using atomic force microscopy, we measure mechanical tension in the basal surface of the wing disc epithelium of Drosophila. We find that basal tension depends on both the actomyosin cytoskeleton and the basement membrane, and that it is proportional to lateral surface tension and hydrostatic pressure. Collagen IV turnover and mobility are slow indicating that the basement membrane can store elastic stresses. Our data suggest that e...
Bulletin of the American Physical Society, 2019
Science, 2020
Rheology of aging protein condensates Protein condensates that form by undergoing liquid-liquid p... more Rheology of aging protein condensates Protein condensates that form by undergoing liquid-liquid phase separation will show changes in their rheological properties with time, a process known as aging. Jawerth et al. used laser tweezer–based active and microbead-based passive rheology to characterize the time-dependent material properties of protein condensates (see the Perspective by Zhang). They found that condensate aging is not gelation of the condensates, but rather a changing viscoelastic Maxwell liquid with a viscosity that strongly increases with age, whereas the elastic modulus stays the same. Science , this issue p. 1317 ; see also p. 1271
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Papers by Elisabeth Fischer-friedrich