bims-ecemfi 2024-07-28 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2024–07–28
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Physical network regimes of 3D fibrillar collagen networks trigger invasive phenotypes of breast cancer cells.
Visualizing the Cell-Matrix Interactions and Cytoskeleton of Disseminated Tumor Cells.
Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.
The structure and mechanics of the cell cortex depend on the location and adhesion state.
Modelling the effect of cell motility on mixing and invasion in epithelial monolayers.
Rigidity percolation and active advection synergize in the actomyosin cortex to drive amoeboid cell motility.
RGD Density on Tadpole Nanostructures Regulates Cancer Stem Cell Proliferation and Stemness.

Biomater Adv. 2024 Jul 16. pii: S2772-9508(24)00204-8. [Epub ahead of print]163 213961

Physical network regimes of 3D fibrillar collagen networks trigger invasive phenotypes of breast cancer cells.

Jiranuwat Sapudom, Philipp Riedl, Maria Schricker, Klaus Kroy, Tilo Pompe.

  The mechanical characteristics of the extracellular environment are known to significantly influence cancer cell behavior in vivo and in vitro. The structural complexity and viscoelastic dynamics of the extracellular matrix (ECM) pose significant challenges in understanding its impact on cancer cells. Herein, we report distinct regulatory signatures in the invasion of different breast cancer cell lines into three-dimensional (3D) fibrillar collagen networks, caused by systematic modifications of the physical network properties. By reconstituting collagen networks of thin fibrils, we demonstrate that such networks can display network strand flexibility akin to that of synthetic polymer networks, known to exhibit entropic rubber elasticity. This finding contrasts with the predominant description of the mechanics of fibrillar collagen networks by an enthalpic bending elasticity of rod-like fibrils. Mean-squared displacement analysis of free-standing fibrils confirmed a flexible fiber regime in networks of thin fibrils. Furthermore, collagen fibrils in both networks were softened by the adsorption of highly negatively charged sulfonated polymers and colloidal probe force measurements of network elastic modulus again proofed the occurrence of the two different physical network regimes. Our cell assays revealed that the cellular behavior (morphology, clustering, invasiveness, matrix metalloproteinase (MMP) activity) of the 'weakly invasive' MCF-7 and 'highly invasive' MDA-MB-231 breast cancer cell lines is distinctively affected by the physical (enthalpic/entropic) network regime, and cannot be explained by changes of the network elastic modulus, alone. These results highlight an essential pathway, albeit frequently overlooked, how the physical characteristics of fibrillar ECMs affect cellular behavior. Considering the coexistence of diverse physical network regimes of the ECM in vivo, our findings underscore their critical role of ECM's physical network regimes in tumor progression and other cell functions, and moreover emphasize the significance of 3D in vitro collagen network models for quantifying cell responses in both healthy and pathological states.

Keywords:  (semi)flexible networks; 3D fibrillar collagen scaffolds; Breast cancer cell invasion; Entropic elasticity; Mechanotransduction

DOI:  https://doi.org/10.1016/j.bioadv.2024.213961
Methods Mol Biol. 2024 ;2811 207-220

Visualizing the Cell-Matrix Interactions and Cytoskeleton of Disseminated Tumor Cells.

Tsukasa Shibue.

  Tumor cells often leave the primary tumor mass and get settled in a foreign tissue years before the development of overt metastases, exhibiting the highly inefficient nature of metastatic colony formation. In fact, the tumor cells that disseminate into distant organs and subsequently invade the parenchyma of these organs rarely proceed to found actively growing metastatic colonies. Instead, the majority of these tumor cells undergo prolonged proliferative arrest unless they are swiftly eliminated by the immune system. Together, these observations indicate that the proliferative capacity of the disseminated tumor cells (DTCs) serves as a key determinant of the efficiency of metastasis, highlighting the need to better understand the mechanism governing the proliferation of these cells. Recent studies are unveiling the importance of the interactions between DTCs and the microenvironment of the host tissue in regulating the proliferation of DTCs. However, the details of such interactions remain to be fully delineated. Here I describe the methods for visualizing and analyzing the interactions between DTCs and the extracellular matrix (ECM) components of the host tissue as well as the cytoskeleton of the DTCs that support these interactions. The methods described here will facilitate the study of how DTCs interact with the ECM of their host tissue, which will be crucial for elucidating the mechanism that underlies the regulation of DTC proliferation by the DTC-ECM interactions.

Keywords:  Disseminated tumor cells (DTCs); ECM remodeling; Ex vivo imaging; Fluorescent probes; Metastatic colonization

DOI:  https://doi.org/10.1007/978-1-0716-3882-8_16
iScience. 2024 Jul 19. 27(7): 110310

Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.

Paras Jain, Ramanarayanan Kizhuttil, Madhav B Nair, Sugandha Bhatia, Erik W Thompson, Jason T George, Mohit Kumar Jolly.

  Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor β (TGF-β) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.

Keywords:  Cancer; Cell biology; Mathematical biosciences

DOI:  https://doi.org/10.1016/j.isci.2024.110310
Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2320372121

The structure and mechanics of the cell cortex depend on the location and adhesion state.

D A D Flormann, L Kainka, G Montalvo, C Anton, J Rheinlaender, D Thalla, D Vesperini, M O Pohland, K H Kaub, M Schu, F Pezzano, V Ruprecht, E Terriac, R J Hawkins, F Lautenschläger.

  Cells exist in different phenotypes and can transition between them. A phenotype may be characterized by many different aspects. Here, we focus on the example of whether the cell is adhered or suspended and choose particular parameters related to the structure and mechanics of the actin cortex. The cortex is essential to cell mechanics, morphology, and function, such as for adhesion, migration, and division of animal cells. To predict and control cellular functions and prevent malfunctioning, it is necessary to understand the actin cortex. The structure of the cortex governs cell mechanics; however, the relationship between the architecture and mechanics of the cortex is not yet well enough understood to be able to predict one from the other. Therefore, we quantitatively measured structural and mechanical cortex parameters, including cortical thickness, cortex mesh size, actin bundling, and cortex stiffness. These measurements required developing a combination of measurement techniques in scanning electron, expansion, confocal, and atomic force microscopy. We found that the structure and mechanics of the cortex of cells in interphase are different depending on whether the cell is suspended or adhered. We deduced general correlations between structural and mechanical properties and show how these findings can be explained within the framework of semiflexible polymer network theory. We tested the model predictions by perturbing the properties of the actin within the cortex using compounds. Our work provides an important step toward predictions of cell mechanics from cortical structures and suggests how cortex remodeling between different phenotypes impacts the mechanical properties of cells.

Keywords:  actin; cells; cortex; cytoskeleton; suspended

DOI:  https://doi.org/10.1073/pnas.2320372121
J Biol Phys. 2024 Jul 20.

Modelling the effect of cell motility on mixing and invasion in epithelial monolayers.

Faris Saad Alsubaie, Zoltan Neufeld.

  Collective cell invasion underlies several biological processes such as wound healing, embryonic development, and cancerous invasion. Here, we investigate the impact of cell motility on invasion in epithelial monolayers and its coupling to cellular mechanical properties, such as cell-cell adhesion and cortex contractility. We develop a two-dimensional computational model for cells with active motility based on the cellular Potts model, which predicts that the cellular invasion speed is mainly determined by active cell motility and is independent of the biological and mechanical properties of the cells. We also find that, in general, motile cells out-compete and invade non-motile cells, however, this can be reversed by differential cell proliferation. Stable coexistence of motile and static cell types is also possible for certain parameter regimes.

Keywords:  Cell competition; Cell motility; Cellular Potts model; Invasion wave

DOI:  https://doi.org/10.1007/s10867-024-09660-8
Dev Cell. 2024 Jul 20. pii: S1534-5807(24)00401-5. [Epub ahead of print]

Rigidity percolation and active advection synergize in the actomyosin cortex to drive amoeboid cell motility.

Juan Manuel García-Arcos, Johannes Ziegler, Silvia Grigolon, Loïc Reymond, Gaurav Shajepal, Cédric J Cattin, Alexis Lomakin, Daniel J Müller, Verena Ruprecht, Stefan Wieser, Raphael Voituriez, Matthieu Piel.

  Spontaneous locomotion is a common feature of most metazoan cells, generally attributed to the properties of actomyosin networks. This force-producing machinery has been studied down to the most minute molecular details, especially in lamellipodium-driven migration. Nevertheless, how actomyosin networks work inside contraction-driven amoeboid cells still lacks unifying principles. Here, using stable motile blebs from HeLa cells as a model amoeboid motile system, we imaged the dynamics of the actin cortex at the single filament level and revealed the co-existence of three distinct rheological phases. We introduce "advected percolation," a process where rigidity percolation and active advection synergize, spatially organizing the actin network's mechanical properties into a minimal and generic locomotion mechanism. Expanding from our observations on simplified systems, we speculate that this model could explain, down to the single actin filament level, how amoeboid cells, such as cancer or immune cells, can propel efficiently through complex 3D environments.

Keywords:  actomyosin; amoeboid migration; biophysics; bleb; cancer; cytoplast; extracellular vesicles; percolation; polymer physics; rheology

DOI:  https://doi.org/10.1016/j.devcel.2024.06.023
Biomacromolecules. 2024 Jul 26.

RGD Density on Tadpole Nanostructures Regulates Cancer Stem Cell Proliferation and Stemness.

Dayong Zhang, Bing Sun, Jingyi Wang, Sung-Po R Chen, Valentin A Bobrin, Yushu Gu, Chun Ki Ng, Wenyi Gu, Michael J Monteiro.

Cancer stem cells (CSCs) make up a small population of cancer cells, primarily responsible for tumor initiation, metastasis, and drug resistance. They overexpress Arg-Gly-Asp (RGD) binding integrin receptors that play crucial roles in cell proliferation and stemness through interaction with the extracellular matrix. Here, we showed that monodisperse polymeric tadpole nanoparticles covalently coupled with different RGD densities regulated colon CSC proliferation and stemness in a RGD density-dependent manner. These tadpoles penetrated deeply and evenly into tumor spheroids and specifically entered cells with cancer stem markers CD24 and CD133. Low RGD density tadpoles triggered integrin α5 expression that further activated TGF-β3 and TGF-β2 signaling pathways, confirmed by the increase of pERK and Bcl-2 protein levels. This process is associated with the RGD cluster presentation controlled by the RGD density on the tadpole surface.

DOI: https://doi.org/10.1021/acs.biomac.4c00645