bims-ecemfi 2025-12-14 papers

Acta Biomater. 2025 Dec 04. pii: S1742-7061(25)00905-5. [Epub ahead of print]

Extracellular matrix physical properties regulate cancer cell morphological transitions in 3D hydrogel microtissues.

Ayda Pourmostafa, Gabrielle Uskach, Mohammad Jafari, Elvan Dogan, Swaprakash Yogeshwaran, Teresa L Wood, Sobhan Ghaeini-Hesaroueiye, Lin Han, Farid Alisafaei, Amir K Miri.

Solid tumor cells can adopt a range of morphological states linked to distinct functional behaviors during tumor progression. Some remain in a proliferative state, forming tight clusters, others detach and elongate into an invasive state, and some retain a rounded amoeboid form with minimal matrix adhesion. However, factors determining which morphological state a cell adopts remain poorly understood. We used a combined theoretical and experimental framework to study how extracellular matrix (ECM) mechanics regulate solid tumor cell morphology in three-dimensional (3D) environments. We developed a theoretical mechanical energy model based on the minimum energy principle, which suggests that a cell will adopt the morphological state (rounded, elongated, or clustered) that minimizes the total energy of the cell-ECM system. Using MDA-MB-231 breast cancer cells, we established a reliable protocol for encapsulating cells into 3D naturally-derived hydrogels with controlled stiffness. We confirmed the model's results in vitro over an extended culture period. In soft ECMs, cells transitioned over time to an elongated morphology, while in stiff ECMs, cells favored clustered configurations. These transitions were governed by the hydrogel-based ECM's physical, not chemical, properties, as confirmed using chemically distinct yet mechanically matched composite matrices. These new insights have implications for solid tumor cell invasion modeling in vitro. STATEMENT OF SIGNIFICANCE: We study the fundamental question of how solid tumor cells adapt their morphology in response to the physical characteristics of the extracellular matrix. This work establishes a robust experimental platform for studying cellular markers in triple-negative breast cancer (TNBC) cells, followed by a biophysical modeling of the cell invasion. Cell clustering was observed in stiffe ECMs, while an elongated morphology was observed in soft ECMs. Our theoretical modeling revealed how the biophysical properties of the matrix can impact cell morphology and invasion behavior. This work can contribute to personalized medicine by making more effective, tailored cancer models.

Keywords: Cancer mechanobiology; Gelatin matrix; Minimum free energy; Remodeling

DOI: https://doi.org/10.1016/j.actbio.2025.12.008

Adv Healthc Mater. 2025 Dec 07. e04086

Hybrid Scaffolds Decouple Biochemical & Biophysical Regulation of Cell Phenotype.

Xinyuan Song, Samantha C Mitchell, Abbie N Smart, William Hardiman, Daniel V Bax, Ceri E Staley, Catherine Probert, Pamela Collier, Marian Meakin, Alison A Ritchie, Tania Mendonca, Amanda J Wright, Victoria James, Anna M Grabowska, Catherine L R Merry, Serena M Best, Ruth E Cameron, Jennifer C Ashworth.

The extracellular matrix changes dramatically during the progression of diseases like cancer. These complex, tissue-specific changes are not adequately replicated by most current biomaterial disease models. This work demonstrates, for the first time, a biomaterial system allowing combined, independent control over stiffness, extracellular matrix composition and 3D collagen architecture. Defined hydrogel formulations are successfully perfused into ice-templated collagen scaffolds, controlling the composition of these hybrid scaffolds at constant stiffness. The Young's moduli of these hybrid scaffolds can also be tuned independently of composition via chemical cross-linking. Encapsulation of human dermal fibroblasts reveals that fibroblast morphology depends on hybrid scaffold composition and on viscoelasticity, highlighting the importance of a system that decouples biophysical from biochemical properties. Finally, these hybrid scaffolds are successfully applied to exert combined control over biochemical and biophysical drivers of cell growth and invasion, focusing on breast cancer as proof-of-concept. The results reveal that collagen fiber patterning enhances breast cancer cell proliferation, also directing the invasion of patient-derived breast cancer cells. These hybrid scaffolds are therefore promising new tools for dissecting the diverse but complementary roles played by the extracellular matrix in regulating cell phenotype, in a range of healthcare applications.

Keywords: breast cancer; collagen scaffold; extracellular matrix; hydrogel; ice‐templating

DOI: https://doi.org/10.1002/adhm.202504086

Nat Commun. 2025 Dec 06.

β-catenin condensation facilitates clustering of the cadherin/catenin complex and formation of nascent cell-cell junctions.

Jooske L Monster, Caterina Manzato, Jan A van der Beek, Willem-Jan Pannekoek, Janneke A Hummelink, Michael A Hadders, Cecilia de Heus, Judith Klumperman, Jurian Schuijers, Martijn Gloerich.

Cadherin-based junctions establish dynamically regulated adhesion between cells to coordinate tissue integrity and morphogenetic movements. Adhesion strength can be modulated by the organization of individual cadherin complexes into lateral clusters. Here, we identify a clustering mechanism of the cadherin complex established by its core component β-catenin. We show that the disordered termini of β-catenin drive the formation of condensates that incorporate other components of the cadherin complex in vitro. Using β-catenin mutants with hampered condensation, we demonstrate that β-catenin condensation nucleates the formation of submicron cadherin/catenin clusters that further develop into stable sites of adhesion. Furthermore, we show that β-catenin-dependent clustering ensures the efficient formation of de novo cell-cell adhesions. Our data thus indicate a role for β-catenin condensates in the supramolecular organization of the cadherin complex, and reveal that the function of β-catenin in the cadherin complex extends beyond connecting cadherin to α-catenin and the actin cytoskeleton.

DOI: https://doi.org/10.1038/s41467-025-66984-2

Theranostics. 2026 ;16(2): 898-914

Nuclear deformation acts as a mechanical switch to drive breast cancer cell migration in a confined microenvironment.

Meng Wang, Xiaodie Li, Boyang Li, Hanyu Guo, Zihan Zhao, Xiyue Sun, Wei Yan, Yubo Tan, Jinyi Liu, Yungchang Chen, Shun Li, Tingting Li, Xiaozhen Dai, Xiang Qin, Yiyao Liu.

Background: Tumour metastasis is the primary cause of high mortality in cancer patients, and the confined migration of cancer cells is the key step in successful metastasis. However, the biomechanical properties of cancer cells during confined migration and the associated mechanotransduction mechanisms remain elusive. In this study, a hydrogel-based microchannel platform was used to investigate the migratory behaviours of breast cancer cells in wide, medium, and narrow microchannels. Methods: Using fluorescence microscopy, we initially characterized MDA-MB-231 breast cancer cells cultured in three distinct hydrogel-based microchannel systems and assessed both whole-cell and nuclear morphology. In parallel, cell migration dynamics were quantified via time-lapse imaging. Immunofluorescence and laser confocal imaging were subsequently employed to systematically analyse the degree of nuclear envelope unfolding and the differential expression of Piezo1. To elucidate the force-sensing mechanism, live-cell calcium imaging was performed to record responses to mechanical stimuli. Ultimately, by constructing plasmids to regulate Lamin A/C expression (knockdown or overexpression) specifically, we demonstrated its role in controlling restricted migration through targeted interference with nuclear shape changes. Results: The results demonstrated that the breast cancer cells displayed the strongest motility in narrow microchannels. Moreover, upon confinement-induced nuclear deformation, the nuclear membranes unfold and tense, which acts as a mechanical switch to facilitate the rapid migration of breast cancer cells in narrow microchannels. Further investigation revealed that the mechanosensitive ion channel Piezo1 was activated on breast cancer cells in narrow microchannels, thereby accelerating calcium influx. This process not only maintained nuclear membrane tension but also activated the cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway, enhancing cell migration via increased myosin II-driven contractility. Conclusions: This study demonstrates the fundamental importance of nuclear deformation and mechanotransduction in cancer cell migration, providing new perspectives for the development of therapeutic approaches that target nuclear mechanics to inhibit metastatic progression.

Keywords: cPLA2-AA pathway; confined migration; mechanotransduction; myosin; nuclear deformation

DOI: https://doi.org/10.7150/thno.119211

J Am Chem Soc. 2025 Dec 11.

Enzyme-Responsive Self-Evolving Hydrogel for Osteochondral Regeneration through Mechanosignaling Pathway.

Yaling Zhuang, Enbo Liu, Yu Gao, Jianxun Ding, Xuesi Chen.

Dynamic and spatially graded mechanical microenvironments are essential for guiding the regeneration of hierarchical osteochondral tissue. Although hydrogels are widely used in stem cells-based tissue regeneration, conventional platforms cannot deliver precisely controlled spatiotemporal mechanical cues required for osteochondral repair. Herein, a self-evolving hydrogel (SE gel) is reported that incorporates a secondary cross-linking network catalyzed by alkaline phosphatase (ALP), formed by the reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys). This enzymatic cross-linking increases network density and complements the primary photo-cross-linking structure, resulting in a 4-fold increase in the storage modulus from 2.73 to 11.08 kPa. The increased stiffness induces a morphological transition in cell spreading from fusiform to polygonal shapes, promotes a 2.2-fold increase in nuclear localization of yes-associated protein (YAP), and triggers osteogenic differentiation. SE gel exploits the endogenous ALP gradient to form a spatially graded, dual-cross-linked network. In the subchondral bone region, a higher ALP activity (∼294.5 U mg-1) catalyzes the extensive formation of a dual-cross-linked structure, whereas the articular cartilage region, with a lower ALP activity (∼15.0 U mg-1), generates a less dense network. This ALP-gradient-driven evolution delivers spatially and temporally dynamic mechanical cues, ranging from soft to stiff, which are transduced through extended integrin-mediated mechanosignaling and subsequently activate the PI3K/AKT/GSK-3β/β-catenin pathway. This cascade regulates key cell functions, such as spreading, migration, and differentiation. The dynamic and gradient-responsive SE gel supports osteochondral regeneration with tissue-specific heterogeneity. To the best of our knowledge, this is the first study to integrate an adaptive hydrogel with an ALP activity gradient, demonstrating its potential in osteochondral regeneration and highlighting the pivotal role of mechanobiology.

DOI: https://doi.org/10.1021/jacs.5c09022

Cell Rep. 2025 Dec 06. pii: S2211-1247(25)01421-4. [Epub ahead of print]44(12): 116649

Context-dependent inhibitory roles of RhoA in 3D invasive cell migration within the extracellular matrix.

Wakiko Iwata, Yoshihiro Adachi, Junior J West, Andrew J Ewald, Yi Zheng, Laura D Wood, Robert A Anders, Hiromi Sesaki, Miho Iijima.

Cell migration is fundamental to both physiological and pathological processes, including cancer progression. This study investigates the role of the small GTPase RHOA in invasive cell migration within diverse 3D extracellular matrix (ECM) environments using non-cancerous HEK293, pancreatic cancer PANC-1, and breast cancer MDA-MB-231 cells. Spheroid invasion assays showed that RHOA loss enhanced migration in HEK293 and PANC-1 cells cultured in Geltrex but not in type I collagen. In contrast, RHOA deletion had little effect on MDA-MB-231 migration in either ECM. Enhanced migration in RHOA-deficient HEK293 cells required protein phosphatase PTP1B and the small GTPases RAC and CDC42. Unexpectedly, while RHOA knockout increased 3D migration, it reduced pancreatic tumor progression in mice. These findings reveal that RHOA regulates cell invasion in a manner dependent on ECM composition and cellular context, highlighting its complex, context-specific roles and potential as a therapeutic target in cancer.

Keywords: 3D cell migration; CP: Cancer; CP: Cell biology; KPC; PDAC; RHOA; cancer; cancer invasion

DOI: https://doi.org/10.1016/j.celrep.2025.116649