bims-ecemfi 2025-02-09 papers

ACS Appl Mater Interfaces. 2025 Feb 06.

Matrix Stiffness Regulates GBM Migration and Chemoradiotherapy Responses via Chromatin Condensation in 3D Viscoelastic Matrices.

Sauradeep Sinha, Mark Fleck, Manish Ayushman, Xinming Tong, Georgios Mikos, Sarah Jones, Luis Soto, Fan Yang.

Glioblastoma multiforme (GBM) progression is associated with changes in matrix stiffness, and different regions of the tumor niche exhibit distinct stiffnesses. Using elastic hydrogels, previous work has demonstrated that matrix stiffness modulates GBM behavior and drug responses. However, brain tissue is viscoelastic, and how stiffness impacts the GBM invasive phenotype and response to therapy within a viscoelastic niche remains largely unclear. Here, we report a three-dimensional (3D) viscoelastic GBM hydrogel system that models the stiffness heterogeneity present within the tumor niche. We find that GBM cells exhibit enhanced migratory ability, proliferation, and resistance to radiation in soft matrices, mimicking the tumor core and perifocal margins. Conversely, GBM cells remain confined and demonstrate increased resistance to chemotherapy in stiff matrices mimicking edematous tumor regions. We identify that stiffness-induced changes in the GBM phenotype are regulated by nuclear mechanosensing and chromatin condensation. Pharmacologically decondensing the chromatin significantly impedes GBM migration and overcomes stiffness-induced chemoresistance and radioresistance. Our findings highlight that stiffness regulates aggressive GBM behavior in viscoelastic matrices through mechanotransduction processes. Finally, we reveal the critical role of chromatin condensation in mediating GBM migration and therapy resistance, offering a potential new therapeutic target to improve GBM treatment outcomes.

Keywords: chromatin condensation; glioblastoma multiforme; mechanotransduction; stiffness; viscoelastic hydrogels

DOI: https://doi.org/10.1021/acsami.4c16993

Mater Today Bio. 2025 Apr;31 101475

Glioblastoma drives protease-independent extracellular matrix invasion of microglia.

Chia-Wen Chang, Ashwin Bale, Rohit Bhargava, Brendan A C Harley.

Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response to GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM conditioned media does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.

Keywords: Brain cancer; Contractility; Extracellular matrix; Immune infiltration; Matrix degradation; Metabolism; Microfluidic

DOI: https://doi.org/10.1016/j.mtbio.2025.101475

Nat Commun. 2025 Feb 04. 16(1): 1365

Visible light-responsive hydrogels for cellular dynamics and spatiotemporal viscoelastic regulation.

Yan Lu, Cheng Chen, Hangyu Li, Peng Zhao, Yuanfeng Zhao, Bohan Li, Wei Zhou, Gaofeng Fan, Dongshi Guan, Yijun Zheng.

Viscoelastic heterogeneity of matrices plays a pivotal role in cancer cell spreading, migration, and metastasis. However, the creation of viscoelastic platforms with spatial-temporal regulation is hindered by cytotoxicity and short regulation durations. Our research presents a dual mechanism for stress relaxation regulation- both intrinsic and responsive- by incorporating Schiff base bonds and a visible light-responsive thiuram disulfide (TDS) moiety into the hydrogel. Modifying base bonds facilitates a broad spectrum of intrinsic stress relaxation times. At the same time, incorporating the visible light-responsive TDS moiety endows the hydrogel with responsive viscoelastic properties. These properties are characterized by minimal cytotoxicity, spatial-temporal controllability, dose dependency, and reversibility. Utilizing this platform, we demonstrate that ovarian cancer cells exhibit contrasting behaviors in contraction and spreading when subjected to dynamic stress relaxation changes over various time periods. Additionally, we observed a "memory effect" in the cell's response to alterations in stress relaxation time. We can spatially direct cell migration through viscoelastic heterogeneity, achieved via photopatterning substrates and laser spots. This innovative approach provides a means to regulate the viscoelasticity of hydrogels across a wide range of timescales, thereby opening avenues for more advanced studies into how cells interpret and respond to spatiotemporal viscoelastic signals.

DOI: https://doi.org/10.1038/s41467-024-54880-0

Eur J Cell Biol. 2025 Jan 27. pii: S0171-9335(25)00002-0. [Epub ahead of print]104(2): 151477

Vitronectin regulates focal adhesion turnover and migration of human placenta-derived MSCs under nutrient stress.

Srishti Dutta Gupta, Nitish Pal, Malancha Ta.

At sites of tissue damage and wound healing, the mesenchymal stem cells (MSCs) are often challenged by nutrient availability due to blood supply disruption. Thus, it becomes critical to identify novel factors and their mechanism of action in regulating the adhesion and migration of MSCs under nutrient stress condition for successful clinical application. In human placenta-derived MSCs (PL-MSCs), we demonstrated an increase in cell spread area, along with increased adhesion and reduced migration of the cells, when cultured under nutrient stress condition. Correspondingly, an increase in the total number per cell and size of focal adhesions (FAs), together with prominent stress fibers were observed in nutrient-stressed PL-MSCs compared to control PL-MSCs. The FAs were demonstrated to be more stable, exhibiting slower turnover and longer lifespan. Vitronectin (VTN), an ECM glycoprotein, was upregulated under nutrient stress condition. Knockdown of VTN in PL-MSCs led to a significant reduction in the total number per cell and size of FAs, along with their faster turnover and shorter lifespan. Subsequently, a reversal in the cell spread area, adhesion and migration properties of the nutrient-stressed PL-MSCs were noted. Additionally, our findings indicated that VTN, as an upstream regulator, stimulated the phosphorylation of myosin light chain, which possibly promoted the maturation and stability of FAs along with assembly of stress fibers, thereby leading to increased adhesion and reduced migration of the cells. Overall, our study defines a distinct role of VTN as a critical regulator of migration in PL-MSCs under nutrient stress condition.

Keywords: Adhesion; Focal adhesions; Migration; Non-muscle myosin II; Placental MSCs; Vitronectin

DOI: https://doi.org/10.1016/j.ejcb.2025.151477