bims-ecemfi 2026-10-18 papers

Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2612028123

Direct physical contacts with epithelial cells regulate leukocyte actin dynamics to facilitate intraepithelial motility in vivo.

Jonathan H Schrope, Tanner F Robertson, Adam Horn, Jack J Stevens, Clyde W Tinnen, Julie Rindy, Nicholas Garcia, Yiran Hou, Emilie Rochon, David J Beebe, Anna Huttenlocher.

Efficient immune cell migration requires physical interactions with surrounding tissues. While tissue matrix mechanics influence leukocyte motility, it is unknown how leukocytes exert pushing and pulling forces to traverse cell-dense epithelial tissues in vivo. Here, we leverage the optical transparency of larval zebrafish to identify how physical interactions with epithelial cells regulate mechanisms of neutrophil force generation to navigate cell-dense tissues. Confining forces from epithelial cells induce a mechanosensitive central actin network, mediated by Cdc42 and Wiskott-Aldrich Syndrome Protein, which exerts expansile forces on surrounding cells to dilate a path for migration. In concert, direct cell-to-cell (leukocyte-epithelial) contacts mediated by integrin ɑE recognition of epithelial cadherin generate traction forces to enable forward motility. Together, our findings identify how physical interactions with the surrounding cellular environment regulate leukocyte motility through epithelial tissue in vivo.

Keywords: actin; cell migration; immunology; neutrophil; zebrafish

DOI: https://doi.org/10.1073/pnas.2612028123

Adv Healthc Mater. 2026 Oct 16. e71844

Macrophage-Fibroblast Crosstalk Governs Tumor Mechanics, as Revealed by Spatiotemporal Force Mapping in 3D Spheroids.

Kunal P Pednekar, Daan Vorselen, Jai Prakash.

Understanding how stromal and immune cells regulate tumor mechanics is essential for deciphering cancer progression and therapy resistance. This study presents a microparticle-based traction force microscopy strategy for in situ quantification of compressive forces within 3D tumor spheroids. Multicellular spheroids composed of tumor cells (T), fibroblasts (F), and macrophages (M) were generated to mimic the tumor microenvironment and to understand the contribution of fibroblast-macrophage crosstalk in tumor mechanobiology. Tri-culture spheroids exhibited the highest proliferative capacity compared to mono- and bi-cultured tumor spheroids. Gene expression profiling indicated strong fibroblast activation, extracellular matrix remodeling, and M2-like macrophage polarization, highlighting a pro-tumoral phenotype. Incorporation of deformable hydrogel microparticles allowed direct mapping of local compressive and indirect quantification of anisotropic stresses. This mapping revealed fibroblasts are the principal source of force generation with the spheroids. Notably, macrophages amplified bulk and anisotropic stresses over two-fold through paracrine activation of fibroblasts. Spatial mapping showed pressure gradients from the core to the periphery, while temporal analyses demonstrated a progressive increase in mechanical stresses with spheroid growth. Together, these findings reveal a surprising governing of intratumoral mechanics by macrophage-fibroblast interactions and demonstrate the potential of microparticle-based 3D force mapping within complex tumor environments.

Keywords: 3D cancer models; extracellular matrix; fibroblasts; force mapping; macrophages; tumor spheroids; tumor stroma

DOI: https://doi.org/10.1002/adhm.71844

Adv Healthc Mater. 2026 Oct 14. e71856

The Role of Viscoelasticity in Heterogeneous Glioblastoma Stem Cell Invasion in Biomimetic 3-Dimensional Hydrogels.

Nicole J Blaine, Arianna Skirzynska, Allysia A Chin, Julie Audet, Molly S Shoichet.

The role of viscoelasticity in cell invasion within the brain extracellular matrix (ECM) is not well understood in the context of glioblastoma (GBM). We designed biomimetic viscoelastic hyaluronan (HA)-based hydrogels to understand the effect of viscoelasticity on the invasion of heterogeneous glioblastoma stem cells (GSCs) categorized into subgroups based on molecular profile, as Reactive, Invasive, or Constructive. Hydrogel viscoelasticity was introduced to a hyaluronan-oxime (HAox) hydrogel to varying degrees through the incorporation of one of methyl cellulose, ECM-based proteins, tenascin C or collagen IV, or hydrazone chemistry. Each HAox-derived viscoelastic hydrogel exhibited significantly higher stress relaxation than HAox. We demonstrated that heterogeneous patient-derived GSC lines respond differently to viscoelasticity, with a strong correlation between greater invasion of Reactive GSCs in faster stress-relaxing matrices. This work highlights the importance of investigating the behavior of GSCs based on their heterogeneous molecular profiles and contributes to the understanding of the role of viscoelasticity in GSC invasion.

Keywords: cell invasion, glioblastoma, glioblastoma stem cells; hyaluronan; hydrogel; viscoelasticity

DOI: https://doi.org/10.1002/adhm.71856

Nat Commun. 2026 Oct 16. pii: 10653. [Epub ahead of print]17(1):

3D confinement physically regulates cell cycle progression in budding yeast.

M Sreepadmanabh, Mridul Gautam, Nikita Bagade, Sunil Laxman, Tapomoy Bhattacharjee.

Our understanding of cell division control traditionally comes via using liquid broths or 2D flat-plate cultures - which cannot recapitulate the complex visco-elasto-plastic properties of natural habitats such as tissues, mucus, and soil. Consequently, how such regimes of physical confinement influence proliferative growth remains poorly understood. Here, using engineered, mechanically tunable and transparent growth matrices, we directly visualize yeast budding and division across 3D viscoelastic regimes. We discover that elevated physical confinement drastically prolongs budding intervals without any physiological defects or activating global regulatory programs. Remarkably, extended cell division times are not associated with transcriptional or proteomic signatures of mechanosensation or cell cycle regulation. Rather, 3D confinement physically constrains the volumetric growth of incipient buds - manifesting as delayed cell cycle progression. Hence, our findings establish that physical constrainment regulates eukaryotic cell division.

DOI: https://doi.org/10.1038/s41467-026-78414-y