bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2024–09–08
thirteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Tuning viscoelasticity and stiffness in bioprinted hydrogels for enhanced 3D cell culture: A multi-scale mechanical analysis.
  2. Plasticity Variable Collagen-PEG Interpenetrating Networks Modulate Cell Spreading.
  3. Confinement controls the directional cell responses to fluid forces.
  4. Photo-induced changes in tissue stiffness alter epithelial budding morphogenesis in the embryonic lung.
  5. Strain-dependent dynamic re-alignment of collagen fibers in skeletal muscle extracellular matrix.
  6. Characterization, enrichment, and computational modeling of cross-linked actin networks in trabecular meshwork cells.
  7. Evaluation of an Inverse Method for Quantifying Spatially Variable Mechanics.
  8. Substrate Curvature Influences Cytoskeletal Rearrangement and Modulates Macrophage Phenotype.
  9. A viscoelastic-stochastic model of cell adhesion considering matrix morphology and medium viscoelasticity.
  10. How well do 3D-printed tissue mimics represent the complex mechanics of biological soft tissues? An example study with Stratasys' cardiovascular TissueMatrix materials.
  11. Modeling glioblastoma tumor progression via CRISPR-engineered brain organoids.
  12. YAP phosphorylation within integrin adhesions: insights from a computational model.
  13. Bulky glycocalyx drives cancer invasiveness by modulating substrate-specific adhesion.
  1. J Mech Behav Biomed Mater. 2024 Aug 22. pii: S1751-6161(24)00328-X. [Epub ahead of print]159 106696
    Tuning viscoelasticity and stiffness in bioprinted hydrogels for enhanced 3D cell culture: A multi-scale mechanical analysis.
    Sarah Pragnere, Edwin-Joffrey Courtial, Frédéric Dubreuil, Elisabeth Errazuriz-Cerda, Christophe Marquette, Emma Petiot, Cyril Pailler-Mattei.
      Bioprinted hydrogels are extensively studied to provide an artificial matrix for 3D cell culture. The success of bioprinting hydrogels relies on fine-tuning their rheology and composition to achieve shear-thinning behavior. However, a challenge arises from the limited viscoelastic and stiffness range accessible from a single hydrogel formulation. Nevertheless, hydrogel mechanical properties are recognized as essential cues influencing cell phenotype, migration, and differentiation. Thus, it is crucial to develop a system to easily modulate bioprinted hydrogels' mechanical behaviors. In this work, we modulated the viscoelastic properties and stiffness of bioprinted hydrogels composed of fibrinogen, alginate, and gelatin by tuning the crosslinking bath solution. Various concentrations of calcium ionically crosslinked alginate, while transglutaminase crosslinked gelatin. Subsequently, we characterized the mechanical behavior of our bioprinted hydrogels from the nanoscale to the macroscale. This approach enabled the production of diverse bioprinted constructs, either with similar elastic behavior but different elastic moduli or with similar elastic moduli but different viscoelastic behavior from the same hydrogel formulation. Culturing fibroblasts in the hydrogels for 33 days revealed a preference for cell growth and matrix secretion in the viscoelastic hydrogels. This work demonstrates the suitability of the method to decouple the effects of material mechanical from biochemical composition cues on 3D cultured cells.
    Keywords:  Bioprinting; Crosslinking; Hydrogels; Stiffness; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.jmbbm.2024.106696
  2. Acta Biomater. 2024 Aug 30. pii: S1742-7061(24)00485-9. [Epub ahead of print]
    Plasticity Variable Collagen-PEG Interpenetrating Networks Modulate Cell Spreading.
    Iris G Mercer, Karen Yu, Alexander J Devanny, Melissa B Gordon, Laura J Kaufman.
      The extracellular matrix protein collagen I has been used extensively in the field of biomaterials due to its inherent biocompatibility and unique viscoelastic and mechanical properties. Collagen I self-assembly into fibers and networks is environmentally sensitive to gelation conditions such as temperature, resulting in gels with distinct network architectures and mechanical properties. Despite this, collagen gels are not suitable for many applications given their relatively low storage modulus. We have prepared collagen-poly(ethylene glycol) [PEG] interpenetrating network (IPN) hydrogels to reinforce the collagen network, which also induces changes to network plasticity, a recent focus of study in cell-matrix interactions. Here, we prepare collagen/PEG IPNs varying collagen concentration and collagen gelation temperature to assess changes in microarchitecture and mechanical properties of these networks. By tuning these parameters, IPNs with a range of stiffness, plasticity and pore size are obtained. Cell studies suggest that matrix plasticity is a key determinant of cell behavior, including cell elongation, on these gels. This work presents a natural/synthetic biocompatible matrix that retains the unique structural properties of collagen networks with increased storage modulus and tunable plasticity. The described IPN materials will be of use for applications in which control of cell spreading is desirable, as only minimal changes in sample preparation lead to changes in cell spreading and circularity. Additionally, this study contributes to our understanding of the connection between collagen self-assembly conditions and matrix structural and mechanical properties and presents them as useful tools for the design of other collagen based biomaterials. STATEMENT OF SIGNIFICANCE: We developed a collagen-poly(ethylene glycol) interpenetrating network (IPN) platform that retains native collagen architecture and biocompatibility but provides higher stiffness and tunable plasticity. With minor changes in collagen gelation temperature or concentration, IPN gels with a range of plasticity, storage modulus, and pore size can be obtained. The tunable plasticity of the gels is shown to modulate cell spreading, with a greater proportion of elongated cells on the most plastic of IPNs, supporting the assertion that matrix plasticity is a key determinant of cell spreading. The material can be of use for situations where control of cell spreading is desired with minimal intervention, and the findings herein may be used to develop similar collagen based IPN platforms.
    Keywords:  Collagen; cell spreading; interpenetrating network; viscoplasticity
    DOI:  https://doi.org/10.1016/j.actbio.2024.08.040
  3. Cell Rep. 2024 Aug 28. pii: S2211-1247(24)01043-X. [Epub ahead of print]43(9): 114692
    Confinement controls the directional cell responses to fluid forces.
    Farshad Amiri, Ayuba A Akinpelu, William C Keith, Farnaz Hemmati, Ravi S Vaghasiya, Dylan Bowen, Razan S Waliagha, Chuanyu Wang, Pengyu Chen, Amit K Mitra, Yizeng Li, Panagiotis Mistriotis.
      Our understanding of how fluid forces influence cell migration in confining environments remains limited. By integrating microfluidics with live-cell imaging, we demonstrate that cells in tightly-but not moderately-confined spaces reverse direction and move upstream upon exposure to fluid forces. This fluid force-induced directional change occurs less frequently when cells display diminished mechanosensitivity, experience elevated hydraulic resistance, or sense a chemical gradient. Cell reversal requires actin polymerization to the new cell front, as shown mathematically and experimentally. Actin polymerization is necessary for the fluid force-induced activation of NHE1, which cooperates with calcium to induce upstream migration. Calcium levels increase downstream, mirroring the subcellular distribution of myosin IIA, whose activation enhances upstream migration. Reduced lamin A/C levels promote downstream migration of metastatic tumor cells by preventing cell polarity establishment and intracellular calcium rise. This mechanism could allow cancer cells to evade high-pressure environments, such as the primary tumor.
    Keywords:  CP: Cell biology; NHE1; actin polymerization; actomyosin contractility; cancer metastasis; chemotaxis; confined migration; hydraulic resistance; mechanosensitive ion channels; nuclear stiffness; upstream migration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114692
  4. bioRxiv. 2024 Aug 26. pii: 2024.08.22.609268. [Epub ahead of print]
    Photo-induced changes in tissue stiffness alter epithelial budding morphogenesis in the embryonic lung.
    Kara E Peak, Poornacharanya Rajaguru, Adil Khan, Jason P Gleghorn, Girgis Obaid, Jacopo Ferruzzi, Victor D Varner.
      Extracellular matrix (ECM) stiffness has been shown to influence the differentiation of progenitor cells in culture, but a lack of tools to perturb the mechanical properties within intact embryonic organs has made it difficult to determine how changes in tissue stiffness influence organ patterning and morphogenesis. Photocrosslinking of the ECM has been successfully used to stiffen soft tissues, such as the cornea and skin, which are optically accessible, but this technique has not yet been applied to developing embryos. Here, we use photocrosslinking with Rose Bengal (RB) to locally and ectopically stiffen the pulmonary mesenchyme of explanted embryonic lungs cultured ex vivo . This change in mechanical properties was sufficient to suppress FGF-10-mediated budding morphogenesis along the embryonic airway, without negatively impacting patterns of cell proliferation or apoptosis. A computational model of airway branching was used to determine that FGF-10-induced buds form via a growth-induced buckling mechanism and that increased mesenchymal stiffness is sufficient to inhibit epithelial buckling. Taken together, our data demonstrate that photocrosslinking can be used to create regional differences in mechanical properties within intact embryonic organs and that these differences influence epithelial morphogenesis and patterning. Further, this photocrosslinking assay can be readily adapted to other developing tissues and model systems.
    DOI:  https://doi.org/10.1101/2024.08.22.609268
  5. Acta Biomater. 2024 Aug 30. pii: S1742-7061(24)00479-3. [Epub ahead of print]
    Strain-dependent dynamic re-alignment of collagen fibers in skeletal muscle extracellular matrix.
    Ross P Wohlgemuth, Sathvik Sriram, Kyle E Henricson, Daryl T Dinh, Sarah E Brashear, Lucas R Smith.
      Collagen fiber architecture within the skeletal muscle extracellular matrix (ECM) is significant to passive muscle mechanics. While it is thought that collagen fibers re-orient themselves in response to changes in muscle length, this has not been dynamically visualized and quantified within a muscle. The goal of this study was to measure changes in collagen alignment across a range of muscle lengths and compare the corresponding alignment to muscle mechanics. We hypothesized that collagen fibers dynamically increase alignment in response to muscle stretching, and this change in alignment is related to passive muscle stiffness. Further, we hypothesized that digesting collagen fibers with collagenase would reduce the re-alignment response to muscle stretching. Using DBA/2J and D2.mdx mice, we isolated extensor digitorum longus (EDL), soleus, and diaphragm muscles for collagenase or sham treatment and decellularization to isolate intact or collagenase-digested decellularized muscles (DCMs). These DCMs were mechanically tested and imaged using second harmonic generation microscopy to measure collagen alignment across a range of strains. We found that collagen alignment increased in a strain-dependent fashion, but collagenase did not significantly affect the strain-dependent change in alignment. We also saw that the collagen fibers in the diaphragm epimysium (surface ECM) and perimysium (deep ECM) started at different angles, but still re-oriented in the same direction in response to stretching. These robust changes in collagen alignment were weakly related to passive DCM stiffness. Overall, we demonstrated that the architecture of muscle ECM is dynamic in response to strain and is related to passive muscle mechanics. STATEMENT OF SIGNIFICANCE: Our study presents a unique visualization and quantification of strain-induced changes in muscle collagen fiber alignment as they relate to passive mechanics. Using dynamic imaging of collagen in skeletal muscle we demonstrate that as skeletal muscle is stretched, collagen fibers re-orient themselves along the axis of stretch and increase their alignment. The degree of alignment and the increase in alignment are each weakly related to passive muscle stiffness. Collagenase treatments further demonstrate that the basis for muscle Extracellular matrix stiffness is dependent on factors beyond collagen crosslinking and alignment. Together the study contributes to the knowledge of the structure-function relationships of muscle extracellular matrix to tissue stiffness relevant to conditions of fibrosis and aberrant stiffness.
    Keywords:  Collagen architecture; Extracellular matrix; Muscle mechanics; Second harmonic generation; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.actbio.2024.08.035
  6. bioRxiv. 2024 Aug 21. pii: 2024.08.21.608970. [Epub ahead of print]
    Characterization, enrichment, and computational modeling of cross-linked actin networks in trabecular meshwork cells.
    Haiyan Li, Devon H Harvey, Jiannong Dai, Steven P Swingle, Anthony M Compton, Chenna Kesavulu Sugali, Kamesh Dhamodaran, Jing Yao, Tsai-Yu Lin, Todd Sulchek, Taeyoon Kim, C Ross Ethier, Weiming Mao.
       Purpose: Cross-linked actin networks (CLANs) are prevalent in the glaucomatous trabecular meshwork (TM), yet their role in ocular hypertension remains unclear. We used a human TM cell line that spontaneously forms fluorescently-labeled CLANs (GTM3L) to explore the origin of CLANs, developed techniques to increase CLAN incidence in GMT3L cells, and computationally studied the biomechanical properties of CLAN-containing cells.
    Methods: GTM3L cells were fluorescently sorted for viral copy number analysis. CLAN incidence was increased by (i) differential sorting of cells by adhesion, (ii) cell deswelling, and (iii) cell selection based on cell stiffness. GTM3L cells were also cultured on glass or soft hydrogel to determine substrate stiffness effects on CLAN incidence. Computational models were constructed to mimic and study the biomechanical properties of CLANs.
    Results: All GTM3L cells had an average of 1 viral copy per cell. LifeAct-GFP expression level did not affect CLAN incidence rate, but CLAN rate was increased from ∼0.28% to ∼50% by a combination of adhesion selection, cell deswelling, and cell stiffness-based sorting. Further, GTM3L cells formed more CLANs on a stiff vs. a soft substrate. Computational modeling predicted that CLANs contribute to higher cell stiffness, including increased resistance of the nucleus to tensile stress when CLANs are physically linked to the nucleus.
    Conclusions: It is possible to greatly enhance CLAN incidence in GTM3L cells. CLANs are mechanosensitive structures that affect cell biomechanical properties. Further research is needed to determine the effect of CLANs on TM biomechanics and mechanobiology as well as the etiology of CLAN formation in the TM.
    DOI:  https://doi.org/10.1101/2024.08.21.608970
  7. J Biomech Eng. 2024 Sep 06. 1-41
    Evaluation of an Inverse Method for Quantifying Spatially Variable Mechanics.
    Daniel Pearce, Colleen Witzenburg.
      Soft biological tissues often function as highly deformable membranes in vivo and exhibit impressive mechanical behavior effectively characterized by planar biaxial testing. The Generalized Anisotropic Inverse Mechanics (GAIM) method links full-field deformations and boundary forces from mechanical testing to quantify material properties of soft, anisotropic, heterogeneous tissues. In this study, we introduced an orthotropic constraint to GAIM to improve the quality and physical significance of its mechanical characterizations. We evaluated the updated GAIM method using simulated and experimental biaxial testing datasets obtained from soft tissue analogs (PDMS and TissueMend) with well-defined mechanical properties. GAIM produced stiffnesses (first Kelvin moduli, K1) that agreed well with previously published Young?s moduli of PDMS samples. It also matched the stiffness moduli determined via uniaxial testing for TissueMend, a collagen-rich patch intended for tendon repair. We then conducted the first biaxial testing of TissueMend and confirmed that the sample was mechanically anisotropic via a relative anisotropy metric produced by GAIM. Next, we demonstrated the benefits of full-field laser micrometry in distinguishing between spatial variations in thickness and stiffness. Finally, we conducted an analysis to verify that results were independent of partitioning scheme. The success of the newly implemented constraints on GAIM suggests notable potential for applying this tool to soft tissues, particularly following the onset of pathologies that induce mechanical and structural heterogeneities.
    DOI:  https://doi.org/10.1115/1.4066434
  8. bioRxiv. 2024 Aug 12. pii: 2024.08.12.607593. [Epub ahead of print]
    Substrate Curvature Influences Cytoskeletal Rearrangement and Modulates Macrophage Phenotype.
    Austin Sovar, Matthew Patrick, Ramkumar T Annamalai.
      Inflammation serves as a critical defense mechanism against pathogens and tissue damage but can lead to chronic diseases, such as cardiovascular disease and diabetes, when dysregulated. Macrophages play a pivotal role in orchestrating inflammatory responses, transitioning from pro-inflammatory M1 to anti-inflammatory M2 phenotypes to resolve inflammation and promote tissue repair. Current approaches to modulate macrophage phenotype predominantly rely on biochemical cues, which may induce systemic side effects. Given the mechanosensitivity of macrophages, this study investigates biophysical cues, specifically substrate curvature, as a localized strategy to regulate macrophage phenotype and minimize systemic repercussions. We hypothesized that substrate curvature influences macrophage immunophenotype by modulating F-actin polymerization. To test this hypothesis, we fabricated spherical microgels with tunable curvatures and characterized their biophysical properties. Our findings indicate that macrophages adhere to microgel surfaces irrespective of curvature, but the curvature significantly alters F-actin dynamics. Furthermore, manipulating cytoskeletal dynamics via selective actin inhibition partially reversed curvature-induced changes in macrophage phenotype. These results underscore the pivotal role of substrate curvature in modulating macrophage behavior and immunophenotype. Overall, our study demonstrates that substrate curvature significantly influences macrophage cytoskeletal dynamics and resulting immunophenotype. This simple approach can be utilized as a localized immunomodulatory treatment for inflammatory diseases.
    DOI:  https://doi.org/10.1101/2024.08.12.607593
  9. Soft Matter. 2024 Sep 06.
    A viscoelastic-stochastic model of cell adhesion considering matrix morphology and medium viscoelasticity.
    Shuying Li, Chuanzhen Huang, Hanlian Liu, Xu Han, Zhichao Wang, Zhuang Chen, Jun Huang, Zhen Wang.
      Quantitative investigation of the adhesive behavior between cells and the extracellular matrix (ECM) through molecular bonds is essential for cell culture and bio-medical engineering in vitro. Cell adhesion is a complex multi-scale behavior that includes temporal and spatial scales. However, the influence of the cell and matrix creep effect and the complex spatial morphology characteristics of the matrix on the cell adhesion mechanism is unclear. In the present study, an idealized theoretical model has been considered, where the adhesion of cells and the matrix is simplified into a planar strain problem of homogeneous viscoelastic half-spaces. Furthermore, a new viscoelastic-stochastic model that considers the morphological characteristics of the matrix, the viscoelasticity of the cell and the viscoelasticity of the substrate was developed under the action of a constant external force. The model characterizes the matrix topographical features by fractal dimension (FD), interprets the effects of FD and medium viscoelasticity on the molecular bond force and the receptor-ligand bond re-association rate and reveals a new mechanism for the stable adhesion of molecular bond clusters by Monte Carlo simulation. Based on this model, it was identified that the temporal and spatial distribution of molecular bond force was affected by the matrix FD and the lifetime and stability of the molecular bond cluster could be significantly improved by tuning the FD. At the same time, the viscoelastic creep effect of the cell and matrix increased the re-association rate of open bonds and could expand the window of stable adhesion more flexibly.
    DOI:  https://doi.org/10.1039/d4sm00740a
  10. J Biomed Mater Res A. 2024 Aug 29.
    How well do 3D-printed tissue mimics represent the complex mechanics of biological soft tissues? An example study with Stratasys' cardiovascular TissueMatrix materials.
    Grace N Bechtel, Colton J Kostelnik, Manuel K Rausch.
      Tissue mimicking materials are designed to represent real tissue in applications such as medical device testing and surgical training. Thanks to progress in 3D-printing technology, tissue mimics can now be easily cast into arbitrary geometries and manufactured with adjustable material properties to mimic a wide variety of tissue types. However, it is unclear how well 3D-printable mimics represent real tissues and their mechanics. The objective of this work is to fill this knowledge gap using the Stratasys Digital Anatomy 3D-Printer as an example. To this end, we created mimics of biological tissues we previously tested in our laboratory: blood clots, myocardium, and tricuspid valve leaflets. We printed each tissue mimic to have the identical geometry to its biological counterpart and tested the samples using identical protocols. In our evaluation, we focused on the stiffness of the tissues and their fracture toughness in the case of blood clots. We found that the mechanical behavior of the tissue mimics often differed substantially from the biological tissues they aim to represent. Qualitatively, tissue mimics failed to replicate the traditional strain-stiffening behavior of soft tissues. Quantitatively, tissue mimics were stiffer than their biological counterparts, especially at small strains, in some cases by orders of magnitude. In those materials in which we tested toughness, we found that tissue mimicking materials were also much tougher than their biological counterparts. Thus, our work highlights limitations of at least one 3D-printing technology in its ability to mimic the mechanical properties of biological tissues. Therefore, care should be taken when using this technology, especially where tissue mimicking materials are expected to represent soft tissue properties quantitatively. Whether other technologies fare better remains to be seen.
    Keywords:  biaxial; blood clot; heart valve leaflets; mode‐I; myocardium; pure shear; simple shear
    DOI:  https://doi.org/10.1002/jbm.a.37787
  11. bioRxiv. 2024 Aug 03. pii: 2024.08.02.606387. [Epub ahead of print]
    Modeling glioblastoma tumor progression via CRISPR-engineered brain organoids.
    Matthew Ishahak, Rowland H Han, Devi Annamalai, Timothy Woodiwiss, Colin McCornack, Ryan T Cleary, Patrick A DeSouza, Xuan Qu, Sonika Dahiya, Albert H Kim, Jeffrey R Millman.
      Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, we develop engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM samples. Integrative single-cell trajectory analysis of both eGBO-derived tumor cells and patient GBM samples revealed the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.
    DOI:  https://doi.org/10.1101/2024.08.02.606387
  12. Biophys J. 2024 Sep 03. pii: S0006-3495(24)00594-0. [Epub ahead of print]
    YAP phosphorylation within integrin adhesions: insights from a computational model.
    Hamidreza Jafarinia, Lidan Shi, Haguy Wolfenson, Aurélie Carlier.
      Mechanical and biochemical cues intricately activate YAP, which is pivotal for the cellular responses to these stimuli. Recent findings reveal an unexplored role of YAP in influencing the apoptotic process. It has been shown that on soft matrices YAP is recruited to small adhesions, phosphorylated at Y357, and translocated into the nucleus triggering apoptosis. Interestingly, YAP Y357 phosphorylation is significantly reduced in larger mature focal adhesions on stiff matrices. Building upon these novel insights, we have developed a stochastic model to delve deeper into the complex dynamics of YAP phosphorylation within integrin adhesions. Our findings emphasize several key points: firstly, increasing the cytosolic diffusion rate of YAP correlates with higher levels of phosphorylated YAP (pYAP), secondly, increasing the number of binding sites and distributing them across the membrane surface, mimicking smaller adhesions, leads to higher pYAP levels, particularly at lower diffusion rates. Moreover, we show that the binding and release rate of YAP to adhesions as well as adhesion lifetimes significantly influence the size-effect of adhesion-induced YAP phosphorylation. The results highlight the complex and dynamic interplay between adhesion lifetime, the rate of pYAP unbinding from adhesions, and dephosphorylation rates, collectively shaping overall pYAP levels. In summary, our work advances the understanding of YAP mechanotransduction and opens avenues for experimental validation.
    Keywords:  YAP phosphorylation; integrin adhesions; particle-based stochastic model
    DOI:  https://doi.org/10.1016/j.bpj.2024.09.002
  13. PNAS Nexus. 2024 Aug;3(8): pgae335
    Bulky glycocalyx drives cancer invasiveness by modulating substrate-specific adhesion.
    Amlan Barai, Niyati Piplani, Sumon Kumar Saha, Sarbajeet Dutta, V Gomathi, Mayank M Ghogale, Sushil Kumar, Madhura Kulkarni, Shamik Sen.
      The majority of the eukaryotic cell surface is decorated with a layer of membrane-attached polysaccharides and glycoproteins collectively referred to as the glycocalyx. While the formation of a bulky glycocalyx has been associated with the cancer progression, the mechanisms by which the glycocalyx regulates cancer invasiveness are incompletely understood. We address this question by first documenting subtype-specific expression of the major glycocalyx glycoprotein Mucin-1 (MUC1) in breast cancer patient samples and breast cancer cell lines. Strikingly, glycocalyx disruption led to inhibition of 2D motility, loss of 3D invasion, and reduction of clonal scattering in breast cancer cells at the population level. Tracking of 2D cell motility and 3D invasiveness of MUC1-based sorted subpopulations revealed the fastest motility and invasiveness in intermediate MUC1-expressing cells, with glycocalyx disruption abolishing these effects. While differential sensitivity in 2D motility is attributed to a nonmonotonic dependence of focal adhesion size on MUC1 levels, higher MUC1 levels enhance 3D invasiveness via increased traction generation. In contrast to inducing cell rounding on collagen-coated substrates, high MUC1 level promotes cell adhesion and confers resistance to shear flow on substrates coated with the endothelial surface protein E-selectin. Collectively, our findings illustrate how MUC1 drives cancer invasiveness by differentially regulating cell-substrate adhesion in a substrate-dependent manner.
    DOI:  https://doi.org/10.1093/pnasnexus/pgae335
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