bims-ecemfi 2025-03-23 papers

bioRxiv. 2025 Mar 03. pii: 2025.02.28.640825. [Epub ahead of print]

Engineered basement membrane mimetic hydrogels to study mammary epithelial morphogenesis and invasion.

Jane A Baude, Megan D Li, Sabrina M Jackson, Abhishek Sharma, Daniella I Walter, Ryan S Stowers.

Reconstituted basement membrane (rBM) products like Matrigel are widely used in 3D culture models of epithelial tissues and cancer. However, their utility is hindered by key limitations, including batch variability, xenogenic contaminants, and a lack of tunability. To address these challenges, we engineered a 3D basement membrane (eBM) matrix by conjugating defined extracellular matrix (ECM) adhesion peptides (IKVAV, YIGSR, RGD) to an alginate hydrogel network with precisely tunable stiffness and viscoelasticity. We optimized the mechanical and biochemical properties of the engineered basement membranes (eBMs) to support mammary acinar morphogenesis in MCF10A cells, similar to rBM. We found that IKVAV-modified, fast-relaxing (τ1/2 = 30-150 s), and soft (E = 200 Pa) eBMs best promoted polarized acinar structures. Clusters became invasive and lost polarity only when the IKVAV-modified eBM exhibited both similar stiffness to a malignant breast tumor (E = 4000 Pa) and slow stress relaxation (τ1/2 = 600-1100 s). Notably, tumor-like stiffness alone was not sufficient to drive invasion in fast stress relaxing matrices modified with IKVAV. In contrast, RGD-modified matrices promoted a malignant phenotype regardless of mechanical properties. We also utilized this system to interrogate the mechanism driving acinar and tumorigenic phenotypes in response to microenvironmental parameters. A balance in activity between β1- and β4-integrins was observed in the context of IKVAV-modified eBMs, prompting further investigation into the downstream mechanisms. We found differences in hemidesmosome formation and production of endogenous laminin in response to peptide type, stress relaxation, and stiffness. We also saw that inhibiting either focal adhesion kinase or hemidesmosome signaling in IKVAV eBMs prevented acinus formation. This eBM matrix is a powerful, reductionist, xenogenic-free system, offering a robust platform for both fundamental research and translational applications in tissue engineering and disease modeling.

DOI: https://doi.org/10.1101/2025.02.28.640825

iScience. 2025 Mar 21. 28(3): 111883

Durotaxis and extracellular matrix degradation promote the clustering of cancer cells.

Mykhailo Potomkin, Oleg Kim, Yuliya Klymenko, Mark Alber, Igor S Aranson.

Early stages of metastasis depend on the collective behavior of cancer cells and their interaction with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic potential than single cells. To explore clustering dynamics, we developed a calibrated computational model describing how motile cancer cells biochemically and biomechanically interact with the ECM during the initial invasion phase, including ECM degradation and mechanical remodeling. The model reveals that cluster formation time, size, and shape are influenced by ECM degradation rates and cellular compliance to external stresses (durotaxis). The results align with experimental observations, demonstrating distinct cell trajectories and cluster morphologies shaped by biomechanical parameters. The simulations provide valuable insights into cancer invasion dynamics and may suggest potential therapeutic strategies targeting early-stage invasive cells.

Keywords: biocomputational method; cancer systems biology; in silico biology

DOI: https://doi.org/10.1016/j.isci.2025.111883

Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2322762122

Cell-matrix feedback controls stretch-induced cellular memory and fibroblast activation.

Yuan Hong, Xiangjun Peng, Haomin Yu, Mohammad Jafari, Delaram Shakiba, Yuxuan Huang, Chengqing Qu, Ermia E Melika, Andrew K Tawadros, Aliza Mujahid, Yin-Yuan Huang, Jacob A Sandler, Kenneth M Pryse, Justin M Sacks, Elliot L Elson, Guy M Genin, Farid Alisafaei.

Mechanical stretch can activate long-lived changes in fibroblasts, increasing their contractility and initiating phenotypic transformations. This activation, critical to wound healing and procedures such as skin grafting, increases with mechanical stimulus for cells cultured in two-dimensional but is highly variable in cells in three-dimensional (3D) tissue. Here, we show that static mechanical stretch of cells in 3D tissues can either increase or decrease fibroblast activation depending upon recursive cell-extracellular matrix (ECM) feedback and demonstrate control of this activation through integrated in vitro and mathematical models. ECM viscoelasticity, signaling dynamics, and cell mechanics combine to yield a predictable, but nonmonotonic, relationship between mechanical stretch and long-term cell activation. Results demonstrate that feedback between cells and ECM determine how cells retain memory of mechanical stretch and have direct implications for improving outcomes in skin grafting procedures.

Keywords: cell-matrix feedback; fibroblasts; mechanical memory; mechanobiology; mechanotransduction

DOI: https://doi.org/10.1073/pnas.2322762122

Small. 2025 Mar 21. e2403242

Mechanical Evolution of Metastatic Cancer Cells in 3D Microenvironment.

Karlin Hilai, Daniil Grubich, Marcus Akrawi, Hui Zhu, Razanne Zaghloul, Chenjun Shi, Man Do, Dongxiao Zhu, Jitao Zhang.

Cellular biomechanics plays a critical role in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells' behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3D in vitro models, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, optical Brillouin microscopy is utilized to longitudinally acquire mechanical images of growing cancerous spheroids over the period of 8 days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, it is demonstrated that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images have been developed, suggesting the mechanical features of cancer cells can potentially serve as a new biomarker in cancer classification and detection.

Keywords: 3D microenvironment; biomechanics; breast cancer; brillouin microscopy; cellular spheroid; metastasis

DOI: https://doi.org/10.1002/smll.202403242

Nat Mater. 2025 Mar 14.

Force transmission is a master regulator of mechanical cell competition.

Andreas Schoenit, Siavash Monfared, Lucas Anger, Carine Rosse, Varun Venkatesh, Lakshmi Balasubramaniam, Elisabetta Marangoni, Philippe Chavrier, René-Marc Mège, Amin Doostmohammadi, Benoit Ladoux.

Cell competition is a tissue surveillance mechanism for eliminating unwanted cells, being indispensable in development, infection and tumourigenesis. Although studies have established the role of biochemical mechanisms in this process, due to challenges in measuring forces in these systems, how mechanical forces determine the competition outcome remains unclear. Here we report a form of cell competition that is regulated by differences in force transmission capabilities, selecting for cell types with stronger intercellular adhesion. Direct force measurements in ex vivo tissues and different cell lines reveal that there is an increased mechanical activity at the interface between two competing cell types, which can lead to large stress fluctuations resulting in upward forces and cell elimination. We show how a winning cell type endowed with a stronger intercellular adhesion exhibits higher resistance to elimination and benefiting from efficient force transmission to the neighbouring cells. This cell elimination mechanism could have broad implications for keeping the strong force transmission ability for maintaining tissue boundaries and cell invasion pathology.

DOI: https://doi.org/10.1038/s41563-025-02150-9