bims-ecemfi 2026-03-29 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–03–29
fifteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Matrix viscoelasticity regulates dermal fibroblast activation in a three-dimensional fibrillar microenvironment.
Dynamic matrix remodeling in boronate ester hydrogels for 3D organoid cultures.
Glutamine-dependent changes in fibroblast-derived extracellular matrix dictate cancer cell behavior.
Aligned Fibronectin Microenvironment Temporally Facilitates Profibrotic Fibroblast Activation via Integrin α5β1.
Nuclear Mechanics and Nuclear Mechanotransduction in Cancer Cell Migration and Invasion.
Interplay between membrane protrusive activities and their adhesion strength regulates cell migration.
Cells Dynamically Adapt Their Nuclear Volumes and Proliferation Rates During Single to Multicellular Transitions.
The Laminin-Derived Peptide C16 Interacts With β1 Integrin, and Is Internalized by Vesicles Through Endocytic Pathway.
The effects of volume exclusion and viscosity on collagen fiber nucleation and network morphology.
A Superhydrophobic 3D Cell Culture System Reveals the Mechanobiological Role of Cancer-Associated Fibroblasts in Prostate Cancer Metastasis.
CAFs-derived LAM332 promotes CTCs formation and survival via ITGA3 and contributes to the metastasis of pancreatic ductal adenocarcinoma.
Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.
Suppressing Cell Migration through Discoidal Bottlebrush Copolymer Nanocarriers.
Integrating traction force microscopy and finite element analysis to assess hiPSC-CM mechanics on micropatterned substrates.
Mechanisms of active wetting and fluidification in epithelial cell collectives.

bioRxiv. 2026 Mar 04. pii: 2026.03.02.709111. [Epub ahead of print]

Matrix viscoelasticity regulates dermal fibroblast activation in a three-dimensional fibrillar microenvironment.

Gianna M Gathman, Maitri M Patel, Daniella I Walter, Ryan S Stowers.

Purpose: Fibrosis is the pathological remodeling of the extracellular matrix (ECM) that is largely orchestrated by activated fibroblasts. The mechanical properties of the ECM change drastically during fibrosis, and fibroblasts become increasingly activated by mechanical environments that mimic the properties of fibrotic tissues. While the effects of increased elastic modulus (stiffness) on fibroblast activation have been well-studied, the impact of changes in viscoelasticity are less clear. Here, we sought to determine how fibroblast activation is altered by changes in viscoelasticity in a three-dimensional, fibrillar microenvironment.
Methods: We employed 3D alginate collagen I hydrogels with independently tunable stiffness and stress relaxation rates. Dermal fibroblasts were encapsulated in hydrogels with four distinct mechanical profiles (soft: 3 kPa or stiff: 10 kPa, fast stress relaxing: τ 1/2 ≈ 160 s or slow stress relaxing: τ 1/2 ≈ 1600 s). We assessed fibroblast activation by changes in cell morphology, expression of key activation markers, and evidence of ECM remodeling.
Results: Fibrillar alginate collagen networks enhanced fibroblast spreading, α-smooth muscle actin stress fiber formation, and fibroblast activation protein-α expression in matrices that were slow relaxing or stiff. The presence of the fibrillar network further enhanced fibroblast activation, independent of the changes driven by matrix viscoelasticity. ECM remodeling was also promoted by slow relaxing matrices, with increased fibronectin deposition and more remodeling of the local collagen fiber network.
Conclusions: Our results demonstrate that fibroblast activation is highly responsive to matrix stress relaxation rate, and that models incorporating fibrillar, viscoelastic networks can provide new insights into the role of ECM mechanics driving fibroblast activation.

DOI: https://doi.org/10.64898/2026.03.02.709111
J Control Release. 2026 Mar 22. pii: S0168-3659(26)00253-1. [Epub ahead of print]394 114851

Dynamic matrix remodeling in boronate ester hydrogels for 3D organoid cultures.

M Neumann, D Kožinec, D Hène, L van Uden, K Schneeberger, L J W van der Laan, J Drost, G G Slaats, M C Verhaar, T Vermonden.

  This study demonstrates the development of a viscoelastic hydrogel-based matrix designed to promote physiological tissue microenvironment in 3D cell cultures, utilizing hyaluronic acid-a natural constituent of the extracellular matrix-as the primary polymer. The use of dynamic covalent chemistry, specifically boronate ester bonds, allows for the creation of a tunable biomimetic material with reversible bonds conducive to cell-mediated matrix remodeling. Poly(vinyl alcohol) was employed as cross-linker to form boronate ester bonds, while the polymerization of methacrylate moieties provided a covalently crosslinked network that further improved scaffold stability. Notably, the dynamic boronate ester containing hydrogels performed better than fully static ones, especially in terms of promoting cell proliferation. The hydrogel enabled successful encapsulation of kidney organoids (tubuloids) and intrahepatic cholangiocyte organoids (ICOs), demonstrating viability, increased proliferation compared to static gels, and self-organization into 3D structures. These results highlight the potential of dynamic boronate ester hydrogels, offering a promising step toward animal-free alternatives for organoid culture.

Keywords:  Boronate ester bonds; Hyaluronic acid; Organoids; Viscoelastic hydrogel

DOI:  https://doi.org/10.1016/j.jconrel.2026.114851
Matrix Biol. 2026 Mar 25. pii: S0945-053X(26)00025-9. [Epub ahead of print]

Glutamine-dependent changes in fibroblast-derived extracellular matrix dictate cancer cell behavior.

Julien Guillard, Jessica Stradley, Kristof Turan, Marta R Storl-Desmond, Shan Lin, Yi-Chia Huang, Kevin Muñoz Forti, Christopher R Weber, Simon Schwӧrer.

  The extracellular matrix (ECM) provides key biochemical and biomechanical cues that govern fundamental cellular processes, including growth and migration. ECM dysregulation and altered cell-matrix interactions are drivers of cancer progression, exemplified by pancreatic ductal adenocarcinoma (PDAC), where an abnormally dense, collagen-rich, and stiff ECM correlates with poor patient outcomes. The PDAC microenvironment is poorly perfused, resulting in altered nutrient availability, yet how this metabolic stress shapes the ECM and its biological activity remains largely unknown. Herein, using murine and patient-derived fibroblasts, we demonstrate that glutamine, a key amino acid depleted in poorly perfused PDAC regions, regulates the biochemical composition, mechanical properties, and biological activity of fibroblast-derived ECM. As glutamine availability decreases, fibroblasts shift from producing an interstitial, mature ECM enriched in fibrillar collagens toward a basement membrane-like ECM. Consistent with these observations, glutamine stress inversely correlates with fibrillar collagen expression in CAFs in patients with PDAC. ECM produced under low glutamine conditions is depleted in collagen I, more elastic, and promotes PDAC cell growth compared to ECM generated under glutamine-rich conditions. Reducing the stiffness of such matrices is sufficient to increase PDAC cell growth. Glutamine-dependent changes in ECM composition, stiffness, and biological activity are driven in part by glutamine-regulated alpha-ketoglutarate availability in fibroblasts. These findings establish nutrient availability as a key regulator of ECM biology and suggest the nutrient-dictated ECM as a novel mechanism by which glutamine stress in the tumor microenvironment shapes cancer cell behavior.

Keywords:  ECM; Glutamine; PDAC; collagen; fibroblast; stiffness

DOI:  https://doi.org/10.1016/j.matbio.2026.03.004
Adv Sci (Weinh). 2026 Mar 24. e00047

Aligned Fibronectin Microenvironment Temporally Facilitates Profibrotic Fibroblast Activation via Integrin α5β1.

Doğuhan Beyatlı, Mika Brown, George-Radu Romanescu, Seungkuk Ahn.

  Excessive, aligned nanofibrous extracellular matrix deposition is a main feature of fibrosis, a pathology indicative of poor prognosis in various chronic diseases. Fibronectin is one of the major nanofibrous extracellular matrix proteins that contribute to tissue homeostasis and repair via its cell surface receptors, integrins. Although mechanosensing of aligned fibronectin by fibroblasts is also implicated in the initiation and progression of fibrogenesis, the mechanisms involved remain uncertain. To investigate how profibrotic cell responses and fibrotic tissue development are triggered through these interactions in vitro, we utilized fibroblasts expressing fibronectin-binding integrins (αV-class and α5β1 integrins) cultured on fibronectin-coated electrospun nanofibers with random or aligned networks. During early adhesion, fibroblasts employ a specific integrin, α5β1 integrin, to respond to the aligned nanofibrous fibronectin microenvironment by strengthening cell and F-actin alignments, nascent focal adhesion, and alpha-smooth muscle actin expression that are signatures of early pro-fibrotic activities. Interestingly, α5β1 integrin-mediated fibronectin alignment sensing continues to form fibrotic tissues at a later stage associated with higher alignment, greater alpha-smooth muscle actin expression, and extensive extracellular matrix deposition. This mechanistic insight paves the way to better understand the role of fibronectin and its properties in pathophysiology, representing a new target for potential applications in drug discovery.

Keywords:  aligned nanofiber; fibroblast; fibronectin; fibrosis; integrin; mechanobiology

DOI:  https://doi.org/10.1002/advs.202600047
Biomolecules. 2026 03 18. pii: 457. [Epub ahead of print]16(3):

Nuclear Mechanics and Nuclear Mechanotransduction in Cancer Cell Migration and Invasion.

Claudia Tanja Mierke.

  Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression.

Keywords:  forces; lamins; mechanobiology; mechanosensing; mechanotransdcution; metastasis; nesprins; nuclear pore complex; softness/stiffness; viscoelasticity

DOI:  https://doi.org/10.3390/biom16030457
Mol Biol Cell. 2026 Mar 25. mbcE25120621

Interplay between membrane protrusive activities and their adhesion strength regulates cell migration.

Indranil Ghosh, Ditipriya Mallick, Ankita Sen, Anwesha Kar, Shilpak Chatterjee, Siddhartha Sankar Jana.

Migratory cells can adopt membrane protrusions like blebbing or lamellipodia for efficient migration. The underlying mechanisms of how switching contributes to cell migration are not clearly understood. Here we found that nonmuscle myosin II (NM II) mediated blebbing to lamellipodia conversion (BLC) increased the speed of migration whereas lamellipodia to blebbing conversion (LBC) decreased it in various cells like cancerous cells, mesenchymal stem cells, and T-lymphocytes. Cells with lamellipodia had larger and greater number of focal adhesions compared with blebbing cells, suggesting a link between adhesion strength with membrane protrusions and migration. Migratory cells seeded on collagen I, but not on poly-L-lysine, exhibited a faster BLC and greater migration speed compared with cells seeded on an uncoated surface. Knockdown of integrinβ1 reduced cell migration but these cells were able to undergo conversion of membrane protrusions, albeit with a substantial delay. These findings suggest that cells can fine tune the migration strategy by controlling NM II-mediated protrusion switching and modulating integrin dependent adhesion strength. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-12-0621
Adv Sci (Weinh). 2026 Mar 23. e24325

Cells Dynamically Adapt Their Nuclear Volumes and Proliferation Rates During Single to Multicellular Transitions.

Vaibhav Mahajan, Keshav Gajendra Babu, Markus Mukenhirn, Antje Garside, Vinita Ajit Kini, Trishla Adhikari, Timon Beck, Byung Ho Lee, Kyoohyun Kim, Carsten Werner, Raimund Schlüßler, Alf Honigmann, Sebastian Aland, Anna Verena Taubenberger.

  Tumor development and progression involve biophysical changes across spatial scales, from the subcellular to the multicellular tissue scale. While cells are known to dynamically regulate their volumes and mechanics in dependence of cell state and function, it is unclear how these properties are controlled in dense multicellular environments like developing tumors. Here, we quantified cell and nuclear volumes of cancer cells forming multicellular spheroids within mechanically tunable biohybrid polymer hydrogels. We quantitatively showed that formation of multicellular structures is associated with marked reductions of cellular and nuclear volumes, cell cycle delays as well as cell mechanical alterations, and that these changes are coupled. Single-to-multicellular transitions led to up to 60% decreases in median nuclear volumes, which was not explained by growth-induced compressive stress. Instead, nuclear volume reductions in emerging clusters arose from cell cycle adaptations, with accumulation of smaller G1-phase cells-reversed by CDK1 inhibition. Additional nuclear downsizing in forming clusters was associated with cell mass density and stiffness increases and reverted upon cell release. Conversely, multicellular-to-single cell transitions during invasion were accompanied by nuclear volume expansion and cell softening. Together, these findings reveal dynamic regulation of cellular and nuclear volumes, mechanics, and cell cycle progression in response to multicellular state.

Keywords:  3D model; cell mechanics; cell volume; multicellularity; spheroid; tumour microenvironment

DOI:  https://doi.org/10.1002/advs.202524325
J Cell Physiol. 2026 Mar;241(3): e70157

The Laminin-Derived Peptide C16 Interacts With β1 Integrin, and Is Internalized by Vesicles Through Endocytic Pathway.

Maria Raquel Unterkircher Galheigo, Raquel Sarmento Mateus, Mario Costa Cruz, Olga Aldana Nora, Basilio Smuczek, Nicolas Jones Villarinho, Julia Moura Bernardi, Maria Aparecida Juliano, Joao Jesus Viana Pinheiro, Vanessa Morais Freitas, Ruy Gastaldoni Jaeger.

  Breast cancer is one of the leading causes of mortality worldwide. The tumor microenvironment plays a critical role in cancer progression. This microenvironment is composed of various cells embedded in the extracellular matrix (ECM). Laminin-111, a major ECM glycoprotein, produces bioactive peptides that influence tumor biology. We have shown that the laminin-derived peptide C16 (KAFDITYVRLKF), located in the short arm of the γ1 chain, regulates migration, invasion, and invadopodia formation in different cancer cells. Our findings suggest that the regulatory mechanisms underlying the effects of C16 are associated with β1 integrin. This prompted us to investigate the interaction between the C16 peptide and β1 integrin in breast cancer cells. We found that breast cancer cells bind to C16 peptide, and this attachment is inhibited by β1 integrin depletion via siRNA. Cellular localization of the C16 peptide was analyzed using transmission electron microscopy (TEM) and time-lapse fluorescence microscopy. TEM revealed that nanogold-conjugated C16 decorated the cell membrane and was localized in intracellular vesicles, indicating peptide endocytosis. Time-lapse confocal microscopy showed that C16 was internalized by breast cancer cells within 2 h of incubation, with this process increasing over time. Based on these observations, we hypothesized that the peptide is endocytosed and directed to the endosome-lysosome pathway for degradation. Time-lapse imaging demonstrated that part of the internalized peptide colocalized with lysosomes in breast cancer cells. This suggests that C16 may be involved in integrin recycling. Furthermore, rhodamine-labeled C16 colocalized with activated β1 integrins. Flow cytometry analysis showed that C16 increased β1 integrin activation starting at 1 h of treatment. In summary, our results suggest that after interacting with the cell membrane and activating β1 integrins, breast cancer cells internalize peptide C16, which plays a role in β1 integrin turnover.

Keywords:  C16 peptide; Laminin‐111; breast cancer; tumor microenvironment; β1 integrins

DOI:  https://doi.org/10.1002/jcp.70157
Acta Biomater. 2026 Mar 19. pii: S1742-7061(26)00183-2. [Epub ahead of print]

The effects of volume exclusion and viscosity on collagen fiber nucleation and network morphology.

Iris G Mercer, Mindle S Paneth, Mathieu Lecarpentier, Laura J Kaufman.

  Protein behavior, including protein-protein association and self-assembly, differs in dilute buffers compared to in the crowded environments that are typical in vivo. We performed a comprehensive study of the impacts of crowding on collagen self-assembly into fibers using a range of polysaccharides and polyethylene glycols (PEG) at volume fractions in the physiological range as well as small molecule analogues of these species. We find that crowding accelerates collagen fiber nucleation in proportion to excluded volume without changes to collagen secondary structure or thermal stability, with the acceleration greater for PEGs than for polysaccharides at the same volume fraction. Additionally, we observed the competing effects of volume fraction and viscosity on nucleation, with volume fraction dominant in setting the collagen fiber nucleation time at high degrees of crowding. We show, consistent with previous findings on collagen gelation as a function of temperature, that fiber and network morphological and mechanical differences in collagen gels formed from these solutions is determined primarily by changes in nucleation time, with short nucleation times leading to softer collagen networks with abundant, thin fibers and long nucleation times resulting in stiffer networks with sparse, thick fiber bundles. STATEMENT OF SIGNIFICANCE: We studied the effects of several macromolecules and small molecule analogues on collagen self-assembly and the resulting fiber and network properties of collagen gels. We observed competing effects of excluded volume and viscosity on collagen nucleation depending on the volume fraction of the co-solute and assert that the morphological changes in the resulting gels are due to changes to nucleation time alone. This work elucidates the various effects of co-solutes on collagen self-assembly and is of use for control of collagen material properties and for understanding crowding and related effects on other self-associating proteins.

Keywords:  Collagen; Crowding; ECM; Self-assembly

DOI:  https://doi.org/10.1016/j.actbio.2026.03.033
Adv Healthc Mater. 2026 Mar 21. e00011

A Superhydrophobic 3D Cell Culture System Reveals the Mechanobiological Role of Cancer-Associated Fibroblasts in Prostate Cancer Metastasis.

Alexandria T Carter, Abigail R Fabiano, Ehsan Aalaei, Jason Deng, Dakota E Rostant, Michael R King.

  The ability to model metastatic dissemination under physiologically relevant mechanical conditions, especially of aggregated circulating tumor cells (CTCs), remains a challenge in cancer research. To address this need, this work presents the Advanced Tumor Landscape Analysis System (ATLAS), a rapidly fabricated, 3D-printed superhydrophobic array platform. ATLAS preserves the hierarchical micro- and nanoscale roughness and low-surface-energy interfaces required for stable superhydrophobicity while greatly reducing fabrication time compared to similar technologies, enabling rapid iteration and broad experimental accessibility. Using a superhydrophobic microwell device, heterotypic tumor-stroma clusters were found to exhibit enhanced survival, sustained proliferation, and coordinated activation of STAT3, AKT1, and NFκB signaling under physiological shear conditions that are lethal to single cancer cells. It was determined that shear exposure reprograms cancer-associated fibroblasts to secrete elevated levels of pro-metastatic cytokines, including IL-11 and CXCL12, with signaling effects that persist well beyond the mechanical stimulus. These findings reveal that mechanical conditioning and activated stromal inclusion jointly drive survival-dominant signaling states characteristic of metastatic fitness. Together, ATLAS establishes a materials-enabled framework for resolving how mechanical forces and multicellular organization converge to shape metastatic behavior, offering a powerful preclinical platform for cancer modeling and translational discovery.

Keywords:  3D model; additive manufacturing; cancer metastasis; cell culture; prostate cancer; superhydrophobicity

DOI:  https://doi.org/10.1002/adhm.202600011
Cell Death Dis. 2026 Mar 25.

CAFs-derived LAM332 promotes CTCs formation and survival via ITGA3 and contributes to the metastasis of pancreatic ductal adenocarcinoma.

Haodong Tang, Wenyuan Shi, Siyuan Tan, Zheng Zhang, Qiannan Zhang, Pengcheng Zhou, Yang Wang, Zhengqing Lei, Fangfang Hu, Shan Gao, Jiahua Zhou.

Metastasis remains the primary cause of mortality in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) are key players in metastasis, yet the mechanisms governing CTCs formation and survival are incompletely understood. Here, we identify ITGA3 as a key driver of CTCs generation and metastatic progression in PDAC. Integrated proteomic and transcriptomic analyses, coupled with clinical specimen validation, revealed that ITGA3 expression positively correlates with CTCs abundance and poor prognosis. Mechanistically, ITGA3 promotes epithelial-mesenchymal transition (EMT), enhances matrix metalloproteinase expression, and facilitates tumor cell detachment, thereby initiating CTCs formation. Importantly, cancer-associated fibroblasts (CAFs) secrete laminin-332 (LAM332), which engages ITGA3 on PDAC cells to promote proliferation and invasion, drive homotypic CTC clustering, and suppress apoptosis, collectively sustaining CTCs' survival. Neutralization of CAFs-derived LAM332 impaired tumor cell proliferation and invasion, disrupted CTC cluster formation, increased apoptosis, reduced hepatic and pulmonary metastasis, and prolonged survival in mouse models. These findings uncover a CAFs-LAM332-ITGA3 axis that orchestrates CTCs formation and survival, and highlight this stromal-tumor interaction as a promising therapeutic target to mitigate metastatic progression in PDAC.

DOI: https://doi.org/10.1038/s41419-026-08642-z
Nat Commun. 2026 Mar 25.

Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.

Zhimin Hu, Hannah E Majeski, Aida Mestre-Farrera, Shirong Cai, Arya Lalezarzadeh, Yichi Zhang, Kei-Ichiro Arimoto, Dong-Er Zhang, Helen Piwnica-Worms, Laurent Fattet, Jing Yang.

Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risks and poor survival. Here we report a unique role of the JAK family kinase TYK2 in suppressing breast cancer metastasis under low ECM stiffness. Genetic or pharmacological inhibition of TYK2 in mammary acini and patient-derived organoids leads to invasion at low stiffness by promoting Epithelial-Mesenchymal Transition, which is independent of cytokine-induced JAK/STAT signaling. TYK2 blockade promotes metastasis in breast tumor cell- and patient-derived xenografts. TYK2 localizes at the plasma membrane via IFNAR1 association under low ECM stiffness, whereas high rigidity causes TYK2 cytoplasmic mislocalization and inactivation. Consistently, normal breast epithelium displays membrane-localized TYK2, whereas invasive breast tumors exhibit cytoplasmic TYK2. These findings uncover a TYK2-dependent mechanism by which ECM rigidity suppresses breast cancer metastasis and underscore the need for breast cancer screening in patients receiving TYK2 inhibitors.

DOI: https://doi.org/10.1038/s41467-026-70518-9
JACS Au. 2026 Mar 23. 6(3): 2089-2099

Suppressing Cell Migration through Discoidal Bottlebrush Copolymer Nanocarriers.

Ping Zeng, Haoxiang Zeng, Jinsu Baek, Byungwoo Yoo, Byeong-Su Kim, Markus Müllner.

  Precise control over two-dimensional (2D) polymer nanostructures remains a fundamental challenge, as polymer self-assembly overwhelmingly favors spherical morphologies. Here, we introduce a topology-driven design strategy that overcomes this limitation, enabling the predictable and modular formation of amorphous polymer nanodiscs. Our strategy decouples nanodisc diameter from bottlebrush chemistry. By systematically varying the length of hydrophobic poly-(ethoxyethyl glycidyl ether) (PEE) side chains in the bottlebrush segment, we obtain precise control over nanodisc diameter while maintaining uniform thickness. This tunability allows investigation of size-dependent cellular interactions using MDA-MB-231 cancer cells. Importantly, we show that nanodiscs can serve as pH-responsive carriers that disassemble under acidic conditions and release ICAM-1 inhibitors (A-205804), resulting in effective suppression of cancer cell migration.

Keywords:  Cancer cell migration; Drug delivery systems; Nanoparticles; Self-assembly; pH-responsive

DOI:  https://doi.org/10.1021/jacsau.6c00206
Biofabrication. 2026 Mar 25.

Integrating traction force microscopy and finite element analysis to assess hiPSC-CM mechanics on micropatterned substrates.

Shayan Jannati, Yasaman Maaref, Yousef Javanmardi, Glen Tibbits, Mu Chiao.

  Traction force microscopy (TFM) is a well-established technique for quantifying the forces that cells exert on their underlying substrates. However, its application to dynamically beating cells-such as cardiomyocytes cultured as two-dimensional (2D) monolayers-remains challenging, particularly when the cells are grown on non-planar or micropatterned substrates. In this study, we present an integrated TFM-finite element analysis (FEA) workflow integrated with dual-plane fluorescence imaging. This approach enables quantification of the stress and strain energy density fields generated by human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured on micropatterned polydimethylsiloxane (PDMS) substrates with tunable stiffness. Substrate stiffness was tuned to mimic both healthy (5~kPa) and fibrotic (50~kPa) cardiac microenvironments. Displacement fields captured from the top and bottom planes of the micropatterns were interpolated and mapped onto a finite element model to reconstruct local stress and strain energy distributions. Results showed that substrate stiffness and micropatterning synergistically modulate cardiomyocyte contractility. Micropatterning promoted cellular alignment and directional force transmission, resulting in anisotropic stress fields and increased strain energy density, particularly on stiff substrates. Moreover, proteomic data revealed a shift from oxidative phosphorylation to glycolysis in cells cultured on stiff micropatterned substrates, consistent with pathological cardiac remodeling. Collectively, these findings demonstrate that soft micropatterned substrates recreate a physiological cardiac microenvironment that supports oxidative metabolism and efficient contractility, whereas stiff micropatterned substrates mimic fibrotic remodeling characterized by enhanced stress generation and glycolytic metabolism. The proposed TFM-FEA platform provides a robust and quantitative framework for studying cardiomyocyte mechanobiology under physiologically relevant conditions and can be readily applied to cardiac tissue engineering, disease modelling, and drug screening.

Keywords:  cardiomyocyte contractility; dual-plane fluorescence imaging; finite element analysis (FEA); human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs); micropatterned PDMS substrate; proteomic analysis; traction force microscopy (TFM)

DOI:  https://doi.org/10.1088/1758-5090/ae573e
Nat Mater. 2026 Mar 23.

Mechanisms of active wetting and fluidification in epithelial cell collectives.

Stefano Marchesi, Chiara Guidolin, Andrew E Massey, Gregoire Lemahieu, Zeno Lavagnino, Galina V Beznoussenko, Alexandre A Mironov, Brenda J Green, Elisa Allievi, Emanuele Martini, Serena Magni, Andrea Ghisleni, Caterina Lomazzi, Andrea Francesco Benvenuto, Andreas Schertel, Diana A van Faassen, Stefano Freddi, Giovanni Bertalot, Dario Parazzoli, Paolo Maiuri, Marina Mapelli, Salvatore Pece, Sara Sigismund, Nils C Gauthier, Elisabetta A Cavalcanti-Adam, Alexander X Cartagena-Rivera, Fabio Giavazzi, Giorgio Scita, Andrea Disanza.

Tissue-level phase transitions are emerging as a crucial mechanism in tumour development and metastasis. When becoming invasive, epithelial tumours undergo a transition from a solid-like state to a more fluid-like one. Although the contributions of cell adhesions, traction forces and cell migration for such behaviour are known, the exact biophysical and molecular mechanisms controlling these transitions are not fully understood. Here we show that breast cancer cell fluidity is regulated by IRSp53, a protein linking plasma membranes to the cytoskeleton. In both two-dimensional monolayers and three-dimensional spheroids, the depletion of IRSp53 increases fluidity and active wetting of the substrate due to a decrease in intercellular friction and enhanced local cell rearrangements. Molecularly, IRSp53 interacts with the junctional protein Afadin to control global tensile state and active wetting, establishing these proteins as key regulators of epithelial collectives' viscosity in breast cancer tumouroids. In breast cancer patient samples, low IRSp53 expression levels and aberrant localization correlate with worse clinical outcomes. These findings support the broader relevance of IRSp53-regulated mechanics in epithelia and their potential prognostic value in cancer.

DOI: https://doi.org/10.1038/s41563-026-02553-2