bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2026–03–22
seventeen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Glutamate Drives Glioblastoma Invasion in Three-Dimensional Hyaluronic Acid Hydrogels.
  2. Stiffness-induced destabilization of adherens junctions inhibits vascular network formation by pulmonary endothelial cells in lung-derived extracellular matrix hydrogels.
  3. Extracellular matrix stiffness drives cutaneous squamous cell carcinoma malignant progression via YAP-dependent glycolysis.
  4. Nonmonotonic rate-dependent adhesion of hydrogels.
  5. Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
  6. Disruption of nuclear-cytoskeletal connection impairs epithelial cell mechanosensing and collective migration.
  7. 3D Soft Hydrogels Induce Human Mesenchymal Stem Cells "Deep" Quiescence.
  8. Macrophages restrict tumor immune infiltration by controlling collagen topography.
  9. A Soft Matrix Microenvironment Promotes Laterally Spreading Tumors via Oxidative Phosphorylation-Dependent Cell Adhesion.
  10. Double Sided Traction Force Microscopy: A Method to Confine Cells for Physiologically Relevant Force Measurements.
  11. Jagged1 regulates extracellular matrix deposition and remodeling in triple-negative breast cancer.
  12. Nudging cell migration from within through microrod-induced morphological deformation.
  13. Timing Mechanotransduction: Mechanically Dynamic Biomaterials Reveal the Temporal Hierarchy of YAP/TAZ Control Nodes.
  14. Obscurin A localizes near the cell membrane to modulate stress fiber dynamics and cell migration.
  15. Hbs and Rst adhesion molecules provide a regional code that regulates cell elimination during epithelial remodeling.
  16. Cellular Snowballing: Cell Adhesion and Migration Drive the Self-Assembly of Cell-Microgel Biohybrid Spheroids.
  17. Powers of magnetic graph matrix: Fourier spectrum, walk compression, and applications.
  1. Tissue Eng Part A. 2026 Jan 10. 19373341251410484
    Glutamate Drives Glioblastoma Invasion in Three-Dimensional Hyaluronic Acid Hydrogels.
    Dana Wilkins, Sanjay Kumar.
      Glioblastoma (GBM) tumors are characterized by an excess of extracellular glutamate, one important source of which is the tumor cells themselves. This abundance of glutamate promotes GBM proliferation, migration, and therapeutic resistance, and causes excitotoxicity in nearby neurons. However, despite glutamate's clear role in promoting GBM aggression, the exact mechanisms through which excess glutamate drives these phenotypes, particularly three-dimensional (3D) invasion, remain incompletely understood. To address this gap, we used a 3D brain-mimetic hyaluronic acid (HA) hydrogel to investigate the role of glutamate signaling in GBM 3D invasion. We demonstrate that inhibiting the glutamate N-methyl-d-aspartate receptor (NMDAR) reduces invasion from 3D tumorspheres, a result that is reproducible across multiple continuous culture models and a patient-derived xenograft cell line. We then conducted glutamate-driven invasion studies in 3D HA-based devices that can be microdissected to isolate and differentially analyze invasive and noninvasive cells. Transcriptomic analysis of invasive, noninvasive, and drug-treated populations of cells reveals that NMDAR inhibition suppresses several pathways associated with the mechanobiology of invasion, including matrix remodeling and collagen deposition. Correspondingly, supplementation with exogenous collagen VI partially rescued 3D invasion. Our work speaks to the potential value of biomaterial platforms for identifying the autocrine and paracrine mechanisms through which neurotransmitters fuel GBM invasion.Impact StatementGlutamate is an abundant signaling molecule in the glioblastoma (GBM) microenvironment and important driver of disease progression; however, the mechanisms through which glutamate promotes invasion in three-dimensional (3D) environments remain poorly understood. By combining engineered hyaluronic acid hydrogel platforms and transcriptomic analysis, we determine that blocking glutamate signaling through the N-methyl-d-aspartate receptor suppresses invasion in 3D by interfering with extracellular matrix remodeling processes. This work highlights the utility of biomaterial platforms in dissecting neurotransmitter signaling in GBM invasion.
    Keywords:  NMDA receptors; collagen VI; glioblastoma; glutamate; hyaluronic acid hydrogels; invasion
    DOI:  https://doi.org/10.1177/19373341251410484
  2. Biomaterials. 2026 Mar 13. pii: S0142-9612(26)00160-2. [Epub ahead of print]331 124136
    Stiffness-induced destabilization of adherens junctions inhibits vascular network formation by pulmonary endothelial cells in lung-derived extracellular matrix hydrogels.
    Meng Zhang, Linda A Brouwer, Janette K Burgess, Martin C Harmsen.
      Extracellular matrix stiffness impacts vascular network formation (VNF), yet underlying molecular mechanosignaling pathways in lung-derived endothelial cells (HPMEC) interacting with lung-derived extracellular matrix (ECM) hydrogels are poorly understood. We show an inverse correlation between ECM stiffness and VNF. Using a novel ECM crosslinking platform to simulate up to stiffnesses of fibrotic lung ECM, we show that stiffness signals are received by FAs, leading to phosphorylation of focal adhesion kinase at Tyr397 (FAK-Y397). These signals are then conveyed through cell-cell adhesion junctions, modulating the integrity and expression of β-catenin at the membrane. As it appears, the mechanosignaling is independent of Wnt or YAP/TAZ pathways. Our findings underscore the role of mechanical signaling in vascular morphology and highlight the significance of cell contractility in this process. This organ-derived ECM model offers basic insights for fundamental research and potential translational applications in understanding vascular remodeling in fibrotic diseases.
    Keywords:  Biomechanics; Disease model; ECM hydrogel; Endothelial cells; Extracellular matrix; Vascularization
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124136
  3. Cell Signal. 2026 Mar 16. pii: S0898-6568(26)00143-9. [Epub ahead of print] 112492
    Extracellular matrix stiffness drives cutaneous squamous cell carcinoma malignant progression via YAP-dependent glycolysis.
    Yuqing Feng, Tong Zhou, Cong Yan, Xi Wang, Bingjie Li, Lin Wang, Yuan Li, Songmei Geng.
      The extracellular matrix (ECM) stiffness is significantly elevated in cutaneous squamous cell carcinoma (cSCC) and positively correlates with Clark level, tumor thickness and poor disease-free survival, implicating ECM stiffness as a driver of cSCC malignant progression. Using clinical samples, hydrogels of different stiffness, and a mouse xenograft model, we demonstrated that ECM stiffening activates the integrin-FAK-YAP mechanotransduction pathway. This activation promotes YAP nuclear translocation and YAP-TEAD1 complex formation, which in turn enhances the transcription of the glycolytic enzyme PKM2. Consequently, PKM2 upregulation drives aerobic glycolysis in cSCC cells, leading to increased proliferation, migration, apoptosis resistance, and EMT progression. Therapeutic inhibition of ECM stiffness, YAP transcriptional activity or glycolysis markedly reduces tumor growth and malignant behaviors in vivo. These findings identify a critical mechano-metabolic signaling cascade driving cSCC malignant progression, providing novel targets for therapeutic intervention against cancers associated with fibrosis and mechanical stress.
    Keywords:  Cutaneous squamous cell carcinoma; Extracellular matrix stiffness; Glycolysis; YAP
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112492
  4. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2536311123
    Nonmonotonic rate-dependent adhesion of hydrogels.
    Dongjing He, Jiahe Huang, Yuhang Hu.
      Hydrogel adhesion underlies a wide range of biological and engineering functions, yet its rate dependence remains poorly understood. Classical adhesive systems exhibit a monotonic increase in adhesion strength with separation rate, a behavior attributed to bond stress relaxation. Here, we show that hydrogels fundamentally deviate from this paradigm. Using atomic force microscopy-based indentation over six orders of magnitude in retraction rate, we find that the pull-off force first decreases and then increases, revealing a distinctly nonmonotonic rate dependence in hydrogels. To explain this behavior, we develop a quantitative model that couples the deformation of the hydrogel with a rate-dependent traction carried by interfacial bonds with distinct association and dissociation kinetics. The model reproduces the full pull-off force spectrum exhibiting the nonmonotonic behavior and predicts the evolution of the contact radius during detachment. In situ confocal microscopy measurements of contact-area dynamics confirm these predictions, providing independent validation of the kinetic mechanism. Together, the experiments and theory reveal that hydrogel adhesion is governed by a competition between time-dependent bond formation, which strengthens adhesion at slow rates, and limited bond relaxation, which enhances traction at fast rates. This interplay produces a broad intermediate regime in which reduced contact time suppresses bond buildup and weakens adhesion. Our findings identify a previously unrecognized adhesion regime in polymeric materials and provide a unified framework for understanding and designing hydrogel interfaces whose performance depends sensitively on rate, contact history, and interfacial bonding kinetics.
    Keywords:  dynamic bonding; hydrogel; rate-dependent adhesion
    DOI:  https://doi.org/10.1073/pnas.2536311123
  5. Cancer Res. 2026 Mar 16.
    Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
    Sanjiban Nath, Debanik Choudhury, Alice Amitrano, Konstantinos Konstantopoulos.
      The mechanical properties of cells and tissues have emerged as important biophysical markers for distinguishing between healthy and diseased states. In cancer, mechanical heterogeneity spans multiple scales, from tissue-level variations to substantial differences between individual tumor cells. The prevailing notion is that metastatic cancer cells are typically elastically softer than their non-malignant counterparts, a feature attributed to their ability to deform, remodel their shape, and navigate dense extracellular matrices and constricting blood vessels. However, cells are not purely elastic materials, but instead they exhibit viscoelastic behavior, in which deformation depends not only on instantaneous stiffness but also on time-dependent internal flow. In this context, Gensbittel and colleagues find that cellular viscosity, rather than elasticity, is a key determinant of cancer cell dissemination and extravasation, providing new insights into the mechanical underpinnings of cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1081
  6. Biophys J. 2026 Mar 13. pii: S0006-3495(26)00214-6. [Epub ahead of print]
    Disruption of nuclear-cytoskeletal connection impairs epithelial cell mechanosensing and collective migration.
    Akash T Shaji, Amit Pathak.
      The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex mediates physical communication between the cytoskeleton to the nucleus, thereby influencing nuclear positioning, transcriptional responses, and cell migration. While prior studies have examined LINC's role in single-cell migration, its impact on collective migration of epithelial cells on surfaces of varying stiffness remains unclear. Here, we disrupted LINC function in MCF10A mammary epithelial cells using an inducible dominant-negative SUN1 construct (SUN1L) that sequesters nesprins. We found that MCF10A mammary epithelial cells with SUN1L expression were slower than wildtype controls on collagen-coated polyacrylamide hydrogels of 0.1, 5, and 50 kPa stiffness. While migration speed of both control and SUN1L cells increased on stiffer substrates, the SUN1L cells displayed lower stiffness sensitivity, indicating impaired mechanosensing after LINC disruption. LINC disruption also altered cell and tissue-scale mechanics: SUN1L cells were smaller, softer, and formed denser epithelial sheets. Alongside these physical changes, LINC disrupted cells showed stronger cell-matrix adhesions and reduced actomyosin contractility. Cytoskeletal perturbations further revealed that SUN1L cells are less reliant on actomyosin activity for sustained migration. These findings highlight how nuclear-cytoskeletal decoupling triggers multiscale physical changes-cell softening, crowding, and altered adhesion dynamics-that collectively impair mechanosensitive migration. Given LINC's implication in laminopathies and cancer, our results provide new insight into how its dysfunction may influence disease progression and collective cell behavior.
    DOI:  https://doi.org/10.1016/j.bpj.2026.03.030
  7. Adv Healthc Mater. 2026 Mar 15. e71001
    3D Soft Hydrogels Induce Human Mesenchymal Stem Cells "Deep" Quiescence.
    David Boaventura Gomes, Timo Rademakers, Ana Filipa Henriques Lourenço, Andrea Calore, Clarissa Tomasina, Denis van Beurden, Jinjie Venema, Bryan Chömpff, Hong Liu, Nicole Bouvy, Sandra Camarero-Espinosa, Lorenzo Moroni.
      It has been reported that cells need a more physiologically relevant micro-environment that allows them to maintain their phenotype. When cultured on 2D tissue culture plates, human mesenchymal stem cells (hMSCs) lose their differentiation capacity and clinical potential. Here, we developed a 3D alginate hydrogel functionalized with the Arg-Gly-Asp (RGD) sequence and having mechanical stiffness mimicking the mechanical properties (<5 kPa) of bone marrow. hMSCs cultured in these hydrogels were halted in G1 phase of the cell cycle and non-proliferative, as shown by flow cytometry and 5-Ethynyl-2'-deoxyuridine (EdU) staining, respectively. Their quiescent state was characterized by an upregulation of enhancer of zeste homolog 1 (EZH1) at the gene level, forkhead box O3 (FoxO3) and cyclin-dependent kinase inhibitor 1B (p27) at the gene and protein levels compared to hMSCs grown in 2D. Studies in 3D hydrogels of collagen or alginate-RGD hydrogels presenting a higher concentration of the peptide revealed that, independently of the concentration of RGD or the chemistry of the adhesion motives, hMSCs cultured in 3D presented a similar phenotype. This phenotype was exclusive to 3D cultures. In 2D, even when cells were serum-deprived and became non-proliferative, the expression of these markers was not observed. We propose that this difference may be the result of mammalian target of rapamycin complex 1 (mTORC1) being downregulated in hMSCs cultured in 3D hydrogels, which induces cells in "deep" quiescence. Our results represent a step forward towards understanding hMSCs quiescence and its molecular pathways, providing more insight for hMSCs cell therapies.
    Keywords:  3D culture; G0; RAPTOR; adult stem cells; deep quiescence; mTOR; mesenchymal stem cell; mesenchymal stromal cell; quiescence
    DOI:  https://doi.org/10.1002/adhm.71001
  8. Sci Immunol. 2026 Mar 20. 11(117): eadw8291
    Macrophages restrict tumor immune infiltration by controlling collagen topography.
    Zoé Fusilier, Alexandra Clément, Franck Simon, Isabel Calvente, Roude Jean-Marie, Mathilde Mathieu, Vincent Calmettes, Florence Piastra-Facon, Yazmina Quintana-Perez, Jeyani George Clement, Lou Crestey, Enola Lumineau, Romane Henninger, Mattia Tonani, Valeria Manriquez, Livia Lacerda Mariano, Léa Bensaid, Perrine de Villemagne, Eliane Piaggio, Vincent Semetey, Sylvie Coscoy, Emanuele Martini, Giorgio Scita, Jean-Christophe Gelly, Johanna Ivaska, Hervé Isambert, Christel Goudot, Paolo Pierobon, Ana-Maria Lennon-Duménil, Hélène D Moreau.
      During tumorigenesis, the extracellular matrix is extensively remodeled. Whereas the impact of such remodeling on tumor growth and invasion is well described, the consequences on immune infiltration are not well understood. Combining tissue imaging and machine learning, we show that immune cell localization in tumors can be predicted by the local topography of fibrillar collagens. Such topographies are dictated by a fibrotic pathway driven by transcription factor 4 (Tcf4) in both cancer and stromal cells, which promotes collagen III deposition and results in intermingled collagen networks that favor intratumor infiltration of T cells and neutrophils. Macrophages inhibit this pathway, highlighting their key structural role in shaping the tumor extracellular matrix. Reanalysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures. Together, our data identify collagen network topographies as a key regulator of tumor-infiltrating immune cells.
    DOI:  https://doi.org/10.1126/sciimmunol.adw8291
  9. Adv Sci (Weinh). 2026 Mar 15. e23872
    A Soft Matrix Microenvironment Promotes Laterally Spreading Tumors via Oxidative Phosphorylation-Dependent Cell Adhesion.
    Jiamin Zhong, Jingyi Lu, Haopeng Li, Jun Zhong, Xiaobei Luo, Yiyi Hu, Xianfei Wang, Pengfei Wang, Yanning Zhang, Zhenjiang Wang, Qiuhua Lai, Zhenyu Chen, Wenting Mi, Wang Tin San-To, Weize Li, Shuping Tan, Qihong Cheng, Ruijia Li, Yida Nie, Side Liu, Bing Huang, Zelong Han.
      Laterally spreading tumors (LSTs) are large, flat, early-stage precancerous colorectal lesions that are frequently overlooked during endoscopic examination and present distinct clinical challenges compared to conventional protruding adenomas (PAs). Despite similar histology, the distinct lateral growth of LSTs suggest underlying molecular differences that remain poorly understood. Here, we comprehensively profiled the molecular signatures, cellular phenotypes, and tumor microenvironments of LSTs, PAs, and adjacent normal tissues (NTs) using single-cell RNA sequencing and spatial transcriptomics, clinical specimens and patient-derived organoid models. LSTs exhibited a more malignant phenotype characterized by transcriptome-inferred high copy number variation (CNV) scores, stronger genetic correlation with colorectal cancer, and downregulation of adhesion molecules. Transcriptomic analyses revealed that this downregulation is closely associated with cytoskeletal depolymerization and enhanced oxidative phosphorylation (OXPHOS). Notably, LSTs reside in a softer extracellular matrix than PAs; organoid modeling indicated this environment promotes OXPHOS and modulates adhesion via the ENTPD1-ADORA2B axis. Integrating these observations, we propose a mechanochemical model where a soft matrix is coupled with OXPHOS and cytoskeletal remodeling through ENTPD1-ADORA2B, coinciding with adhesion suppression. These findings provide integrative insights into potential regulatory dynamics underlying LST lateral growth and highlight the ENTPD1-ADORA2B axis for future mechanistic investigation.
    Keywords:  adenomas; colorectal neoplasms; extracellular matrix; laterally spreading tumors; oxidative phosphorylation; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202523872
  10. Cytoskeleton (Hoboken). 2026 Mar 19. e70129
    Double Sided Traction Force Microscopy: A Method to Confine Cells for Physiologically Relevant Force Measurements.
    Alexia Caillier, Patrick W Oakes.
      In this paper we describe a technique to make a confined environment of variable stiffness that is suitable for high-resolution live-cell imaging. This versatile and adaptable technique enables cell confinement between soft elastic surfaces made from polyacrylamide gels. The two surfaces retain all their compatibility with multiple approaches to chemically couple adhesion proteins, and additional techniques like micropatterning and traction force microscopy. This method is thus well suited for measuring force production and migration of weakly adherent cells that struggle to migrate in traditional planar environments.
    Keywords:  cellular confinement; live‐cell; traction force microscopy
    DOI:  https://doi.org/10.1002/cm.70129
  11. Sci Adv. 2026 Mar 20. 12(12): eaea9562
    Jagged1 regulates extracellular matrix deposition and remodeling in triple-negative breast cancer.
    Marjaana Parikainen, Ujjwal Suwal, Pekka Rappu, Jyrki Heino, Cecilia M Sahlgren.
      The extracellular matrix (ECM) and tumor microenvironment heterogeneity drive cancer progression and treatment resistance. High Jagged1 expression correlates with poor patient survival and promotes tumor growth and invasion in triple-negative breast cancer (TNBC). Using transcriptomics, proteomics, and imaging of cancer cell/fibroblast cocultures in vitro and in vivo, we demonstrate that Jagged1-mediated cross-talk between TNBC cells and fibroblasts enhances myofibroblast activation, collagen accumulation, and alignment of ECM fibers. In single-cell RNA sequencing data of TNBC tumors, high Jagged1 expression gives rise to a myofibroblast subpopulation previously associated with enhanced invasion. Jagged1 increases transforming growth factor-β (TGFβ) activity in fibroblast cocultures, and TGFβ inhibition prevents the Jagged1-induced ECM alignment. Thus, Jagged1 regulates ECM remodeling upstream of TGFβ. Furthermore, higher substrate stiffness up-regulates Jagged1, suggesting a feed-forward loop between Jagged1, ECM stiffness, and TGFβ. With the emergence of safe therapeutics targeting specific Notch components, Jagged1 modulation may offer an approach for treating invasive breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.aea9562
  12. Soft Matter. 2026 Mar 17.
    Nudging cell migration from within through microrod-induced morphological deformation.
    Masayuki Hayakawa, Tatsuya Tanaka, Hiroaki Suzuki.
      Cell migration plays a central role in various biological processes, including development, wound healing, and cancer metastasis, and represents a fundamental form of self-organized motion at the cellular scale. These self-propelled cells can serve as microscale agents with potential applications in bioengineering and microsystem design. To realize such possibilities, it is essential to establish effective methods for controlling their migration. Conventional approaches, such as chemotactic, optogenetic, and substrate-based guidance, depend on external interventions that influence only a limited number of cells. Here, we present a proof-of-concept in Dictyostelium discoideum to bias cell migration by inducing deformation from within the cell. We demonstrate that glass microrods are internalized and that these internalized rods elongate the cells along their own axis. The elongated cells tend to migrate in the direction of their long axis, resulting in enhanced directional persistence. Unlike conventional methods requiring external deterministic cues or patterned environments, our approach enables cells to autonomously and persistently alter their migration behavior through internal morphological deformation. This study introduces a new framework for modulating cell migration and establishes a foundation for developing biohybrid systems that utilize living cells as self-propelled carriers.
    DOI:  https://doi.org/10.1039/d5sm01149c
  13. Adv Sci (Weinh). 2026 Mar 19. e15210
    Timing Mechanotransduction: Mechanically Dynamic Biomaterials Reveal the Temporal Hierarchy of YAP/TAZ Control Nodes.
    Alessandro Gandin, Giada Vanni, Veronica Torresan, Margherita Pelosin, Rebecca Busetto, Anna Citron, Ambela Suli, Paolo Contessotto, Carlo Albanese, Francesca Zanconato, Tito Panciera, Stefano Piccolo, Giovanna Brusatin.
      Mechanotransduction is a cardinal regulator of cell behavior, yet its temporal unfolding and hierarchy remain poorly defined. Here, we develop dynamically softening polyacrylamide hydrogels that enable in situ modulation of substrate stiffness across physiological ranges while preserving integrin-mediated adhesion. Time-resolved analyses reveal a biphasic response to extracellular softening. YAP/TAZ are abruptly inactivated at an early stiffness threshold, coincident with rapid collapse of the subnuclear adhesion-F-actin-LINC nucleo-cytoskeletal continuum. At this step, peripheral focal adhesions remain unexpectedly resilient, persisting while undergoing centripetal remodeling. Disrupting SUN2 lowers the mechanosensitive threshold, whereas increased contractility raises it, still in LINC-dependent manner. Early YAP/TAZ shutoff is accompanied by rapid microtubule reorganization away from a centrosomal aster, and by AMOT accumulation. Changes in nuclear flattening, cell rounding, and peripheral adhesion collapse emerge later at lower stiffness thresholds. Mechanotransduction is directionally asymmetric when cells are challenged in situ: YAP/TAZ switch off abruptly at a defined softness threshold, whereas reactivation is efficiently achieved only by cyclic (not static) strain, consistent with ratchet-like temporal integration. Together, these findings establish a spatiotemporal framework for dynamic mechanotransduction and prioritize the nodes that operate on physiologically relevant timescales, providing timing-based constraints to distinguish initiating events from downstream adaptations.
    Keywords:  YAP/TAZ; cell culture; dynamic hydrogels; mechanotransduction; subnuclear adhesion
    DOI:  https://doi.org/10.1002/advs.202515210
  14. J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00253-X. [Epub ahead of print] 111383
    Obscurin A localizes near the cell membrane to modulate stress fiber dynamics and cell migration.
    Kamrin D Shultz, Stephanie N Ouderkirk, Yasmin F Al Anbari, C Jackson White, Peter Henry, Kristopher E Kubow, Daniel E Conway, Callie J Miller, Nathan T Wright.
      Obscurin is a giant (720-900 kDa) modular cytoskeletal protein with multiple signaling domains. While it is most highly expressed in myocytes, obscurin is also the second most mutated protein in breast and colorectal cancers and is significantly downregulated in pancreatic cancer. Obscurin derives its antioncogenic properties, at least in part, through its ability to modulate cellular motility and migration; obscurin knockdown in cultured epithelial cells leads to increased migration and an epithelial-to-mesenchymal transition (EMT). Obscurin likely controls cell motility through the obscurin RhoGEF domain interaction with the RhoA/ROCK pathway and/or the obscurin PH domain interaction with a PI3K/PIP3 pathway. Here, we more fully describe which obscurin domains dictate subcellular localization and regulate cellular motility. The obscurin C-terminus adenovirally infected into MDCK and MCF-10A cells localizes to adhesion structures at the plasma membrane. This localization is driven by four regions in obscurin: the obscurin RhoGEF and PH domains, along with two regions in the unstructured C-terminus. Infected cells lack central stress fibers, and this morphology is linked to the RhoGEF domain, the PH domain, and the C-terminal 76 residues. These three obscurin regions also inhibit cell motility. Together these data demonstrate how both specific obscurin domains and specific cellular localization regulate cellular velocity.
    Keywords:  EMT; Obscurin; PIP(3); actin; cancer; cell migration; confocal microscopy; metastasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111383
  15. iScience. 2026 Mar 20. 29(3): 114971
    Hbs and Rst adhesion molecules provide a regional code that regulates cell elimination during epithelial remodeling.
    Miguel Ferreira-Pinto, Mario Aguilar-Aragón, Christa Rhiner, Eduardo Moreno.
      Cellular interactions and mechanical forces are fundamental in shaping epithelial tissue architecture. In the Drosophila notum, tissue compression at the midline promotes epithelial cell elimination. Here, we conducted a multi-step RNAi screen and identified 47 diverse regulators of notum epithelial remodeling. We find that the two cell adhesion proteins Hibris (Hbs) and Roughest (Rst) show high expression in zones of cell survival versus low levels in areas of cell pruning. Notum-wide knock-down of hbs or rst or homogenous hbs overexpression disrupts cell death patterns and results in adult tissue malformations. Local suppression of Hbs and Rst in Hbshigh/Rsthigh territories triggers ectopic cell elimination indicating that Hbs/Rst can instruct cell removal. Interestingly, Hbs but not Rst is regulated by compaction-sensitive EGFR signaling, positioning Hbs as an integrator of both mechanical and cell property cues. These findings uncover a novel adhesive landscape that shapes the thorax midline and potentially other organs.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114971
  16. Adv Sci (Weinh). 2026 Mar 17. e11302
    Cellular Snowballing: Cell Adhesion and Migration Drive the Self-Assembly of Cell-Microgel Biohybrid Spheroids.
    Zaman Ataie, Sina Kheirabadi, Changhao Li, Aneesh Risbud, Aswathy Sebastian, Istvan Albert, Sulin Zhang, Amir Sheikhi.
      Creating three-dimensional (3D) tissue models using cell spheroids that recapitulate the complicated structures and functions of human tissues is essential for advancing new approach methodologies used in drug testing/screening, disease modeling, and regenerative medicine. However, cell spheroids often have dense cellular structures and subsequently poor cell survival, primarily due to impaired oxygen and metabolite transport. To overcome these limitations, we develop biohybrid spheroids (BHS), self-assembled living-synthetic hybrid aggregates, using adherent cells as assembly engines and hydrogel microparticles (microgels) as extracellular matrix-mimetic substrates. We show the revolving assembly of 3D BHS, driven by progressive cell migration and adhesion via culturing adherent mammalian cells and gelatin methacryloyl microgels, reminiscing a snowballing effect. The aggregation kinetics and terminal size of BHS are tailored by adjusting microgel size and cell-to-microgel ratio. Notably, microgels significantly larger than the cells yield porous, millimeter-sized BHS, facilitating molecular diffusion and improving cell viability. Furthermore, transcriptional analyses show shifts in adhesion, angiogenesis, hypoxia, and proliferation programs in BHS compared with cell spheroids. An agent-based model is developed to recapitulate the snowballing assembly in a geometrically unconstrained environment, providing fundamental insights into the assembly kinetics and the ultimate BHS size and pore features. BHS may open new opportunities for developing predictive and scalable technologies to self-assemble large-scale physiologically relevant tissue models in vitro, potentially transforming the biofabrication of microphysiological systems.
    Keywords:  granular hydrogel; living material; microgel; new approach methodologies; spheroid; tissue engineering
    DOI:  https://doi.org/10.1002/advs.202511302
  17. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2516664123
    Powers of magnetic graph matrix: Fourier spectrum, walk compression, and applications.
    Yinan Huang, David F Gleich, Pan Li.
      Magnetic graphs, originally developed to model quantum systems under magnetic fields, have recently emerged as a powerful framework for analyzing complex directed networks. Existing research has primarily used the spectral properties of the magnetic graph matrix to study global and stationary network features. However, their capacity to model local, nonequilibrium behaviors, often described by matrix powers, remains largely unexplored. We present a combinatorial interpretation of the magnetic graph matrix powers through directed walk profiles-counts of graph walks indexed by the number of edge reversals. Crucially, we establish that walk profiles correspond to a Fourier transform of magnetic matrix powers. The connection allows exact reconstruction of walk profiles from magnetic matrix powers at multiple discrete potentials, and more importantly, an even smaller number of potentials often suffices for accurate approximate reconstruction in real networks. This shows the empirical compressibility of the information captured by the magnetic matrix. This fresh perspective suggests further applications; for example, we illustrate how powers of the magnetic matrix can identify frustrated directed cycles (e.g., feedforward loops) and can be effectively employed for link prediction by encoding local structural details in directed graphs.
    Keywords:  complex networks; compressibility; directed graphs; magnetic graph matrix
    DOI:  https://doi.org/10.1073/pnas.2516664123
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