Extracellular matrix viscoelasticity regulates TGFβ1‐induced epithelial‐mesenchymal transition and apoptosis via integrin linked kinase

Sacco, Jessica L.; Vaneman, Zachary T.; Gomez, Esther W.

doi:10.1002/jcp.31165

Cited by 5 publications

References 62 publications

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Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

Sankhe,

Sacco,

Lawton

et al. 2024

Advanced Biology

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Mesenchymal–epithelial transition (MET) is essential for tissue and organ development and is thought to contribute to cancer by enabling the establishment of metastatic lesions. Despite its importance in both health and disease, there is a lack of in vitro platforms to study MET and little is known about the regulation of MET by mechanical cues. Here, hyaluronic acid‐based hydrogels with dynamic and tunable stiffnesses mimicking that of normal and tumorigenic mammary tissue are synthesized. The platform is then utilized to examine the response of mammary epithelial cells and breast cancer cells to dynamic modulation of matrix stiffness. Gradual softening of the hydrogels reduces proliferation and increases apoptosis of breast cancer cells. Moreover, breast cancer cells exhibit temporal changes in cell morphology, cytoskeletal organization, and gene expression that are consistent with mesenchymal–epithelial plasticity as the stiffness of the matrix is reduced. A reduction in matrix stiffness attenuates the expression of integrin‐linked kinase, and inhibition of integrin‐linked kinase impacts proliferation, apoptosis, and gene expression in cells cultured on stiff and dynamic hydrogels. Overall, these findings reveal intermediate epithelial/mesenchymal states as cells move along a matrix stiffness‐mediated MET trajectory and suggest an important role for matrix mechanics in regulating mesenchymal–epithelial plasticity.

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Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

Sankhe,

Sacco,

Lawton

et al. 2024

Advanced Biology

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Intraoperative Cavity Local Delivery System with NETs‐Specific Drug Release for Post‐Breast Cancer Surgery Recurrence Correction

Zhu,

Ji,

Wang

et al. 2024

Adv Healthcare Materials

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Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors‐β (TGF‐β) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio‐safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF‐β at tumor‐resection sites, whose unique mechanism for local TGF‐β amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti‐TGF‐β. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF‐β and related indicators, impeding epithelial‐mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.

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Stress relaxation rates of myocardium from failing and non-failing hearts

Gionet-Gonzales,

Gathman,

Rosas

et al. 2024

Preprint

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The heart is a dynamic pump whose function is influenced by its mechanical properties. The viscoelastic properties of the heart, i.e. its ability to exhibit both elastic and viscous characteristics upon deformation, influence cardiac function. Viscoelastic properties change during heart failure (HF), but, direct measurements of failing and non-failing myocardial tissue stress relaxation under constant displacement are lacking. Further, how consequences of tissue remodeling, such as fibrosis and fat accumulation, alter the stress relaxation remains unknown. To address this gap, we conducted stress relaxation tests on porcine myocardial tissue to establish baseline properties of cardiac tissue. We found porcine myocardial tissue to be fast relaxing, characterized by stress relaxation tests on both a rheometer and microindenter. We then measured human left ventricle (LV) epicardium and endocardium human tissue from non-failing, ischemic HF, and non-ischemic HF patients by microindentation. We found that the ischemic HF had slower stress relaxation than non-failing endocardium; and that slower stress relaxing tissues were correlated with increased collagen deposition and increased α-smooth muscle actin (α-SMA) stress fibers, a marker of fibrosis and cardiac fibroblast activation, respectively. In the epicardium, we found that ischemic HF had faster stress relaxation than non-ischemic HF and non-failing; and that faster stress relaxation correlated with Oil Red O staining, a marker for adipose tissue. These data show that changes in stress relaxation vary across the different layers of the heart during ischemic vs. non-ischemic HF. These findings reveal how the viscoelasticity of the heart changes, which will lead to better modeling of cardiac mechanics for in vitro and in silico HF models.

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Extracellular matrix viscoelasticity regulates TGFβ1‐induced epithelial‐mesenchymal transition and apoptosis via integrin linked kinase

Cited by 5 publications

References 62 publications

Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

Intraoperative Cavity Local Delivery System with NETs‐Specific Drug Release for Post‐Breast Cancer Surgery Recurrence Correction

Stress relaxation rates of myocardium from failing and non-failing hearts

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