Extracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells
Claudia Tanja Mierke
Abstract:Extracellular biophysical properties have particular implications for a wide spectrum of cellular behaviors and functions, including growth, motility, differentiation, apoptosis, gene expression, cell–matrix and cell–cell adhesion, and signal transduction including mechanotransduction. Cells not only react to unambiguously mechanical cues from the extracellular matrix (ECM), but can occasionally manipulate the mechanical features of the matrix in parallel with biological characteristics, thus interfering with … Show more
“…Collagen receptors and their downstream signaling pathways in astrocytes could potentially sense and respond to mechanical stimuli from the surrounding extracellular matrix (ECM). Type IV and Type XIII collagen likely contribute to the mechanical properties of the ECM, influencing astrocyte behavior such as migration, proliferation, and differentiation in response to changes in tissue stiffness or mechanical stress. , …”
Section: Resultsmentioning
confidence: 99%
“…Type IV and Type XIII collagen likely contribute to the mechanical properties of the ECM, influencing astrocyte behavior such as migration, proliferation, and differentiation in response to changes in tissue stiffness or mechanical stress. 56 , 57…”
After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion "core" and peripheral "pericontusional" regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear.Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan + , Brevican + , and Neurocan + astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.
“…Collagen receptors and their downstream signaling pathways in astrocytes could potentially sense and respond to mechanical stimuli from the surrounding extracellular matrix (ECM). Type IV and Type XIII collagen likely contribute to the mechanical properties of the ECM, influencing astrocyte behavior such as migration, proliferation, and differentiation in response to changes in tissue stiffness or mechanical stress. , …”
Section: Resultsmentioning
confidence: 99%
“…Type IV and Type XIII collagen likely contribute to the mechanical properties of the ECM, influencing astrocyte behavior such as migration, proliferation, and differentiation in response to changes in tissue stiffness or mechanical stress. 56 , 57…”
After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion "core" and peripheral "pericontusional" regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear.Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan + , Brevican + , and Neurocan + astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.
“…The surface roughness and patterning of the ECM can also affect cell motility, sensing capabilities, and the development of cellular structures [ 61 ]. The translation of mechanical cues from ECM stiffness and topography into cellular actions occurs through mechanotransduction pathways [ 62 ], which modulate gene expression, cell cycle progression, and apoptosis, tailoring cellular responses to the mechanical environment [ 63 ]. Fig.…”
Background
Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation.
Main text
Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs.
Conclusions
This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.
“…EMT and unjamming state transition lead to a reduction in cell-cell adhesion and an increase in motility, which ultimately impairs tissue integrity. This phenomenon facilitates tumor growth and cancer cell invasion, resulting in decreased cancer cell stiffness ( 139 ).…”
Section: Tumor State Transition Driven By Microenvironment Forcesmentioning
The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.
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