Search Results (255)

The cardiac extracellular matrix (ECM) is a dynamic, mechanically active network continuously shaped and interpreted by cardiomyocytes, fibroblasts, and macrophages. Interdependent mechanosensing, force transmission, and ECM remodeling functions create multicellular feedback loops that control tissue stiffness, alignment, maturation, and fibrotic remodeling. Together, these biomechanical processes create reciprocal signaling pathways in which cellular behavior modifies the ECM while the ECM’s mechanics concurrently shape cellular phenotype and function. This review explores cell–ECM mechanoreciprocity, a physiologic framework that unifies cell-sensing mechanotransduction, mechano-electrical coupling, and ECM-based biochemical signaling with cell-driven ECM remodeling. We propose three interconnected feedback loops that integrate biochemical and mechanical cues across cell types: load amplification, structural alignment, and immune regulation. We discuss how advanced two- and three-dimensional engineered cardiac systems incorporating tunable and dynamic mechanical cues can be used to model these interactions. We address the limitations of existing experimental platforms and the need for better models to fully recapitulate in vivo complexities. Understanding and recreating these reciprocal mechanical interactions will provide essential frameworks for disease modeling and therapeutic development while reducing reliance on in vivo studies. Full article

This is a narrative conceptual paper, not a systematic review. Ultrasound-guided fascial hydrorelease (FHR) has been reported to provide sustained pain relief in patients with chronic musculoskeletal pain; however, its underlying biological mechanisms remain incompletely understood. In this paper, we propose the “Fascial Memory Reset Hypothesis” as an integrative framework linking mechanobiology, extracellular matrix (ECM) remodeling, peripheral nociception, microcirculatory dynamics, and ultrasound imaging findings. Mechanobiological research has demonstrated that increased tissue stiffness activates YAP/TAZ signaling, promoting fibroblast activation, ECM deposition, and mechano-epigenetic regulation. These mechanically driven processes can stabilize pathological tissue phenotypes without DNA sequence alterations. The “Fascial Memory Reset Hypothesis” proposes that targeted mechanical interventions such as FHR may partially reverse these mechanically maintained states by restoring tissue mobility and modifying stiffness-dependent mechanotransduction. We propose that “stacking fascia” (observed as layered hyperechoic bands on ultrasound) represents the macroscopic structural phenotype of mechano-epigenetic memory formed through sustained mechanical stress. Integrating molecular mechanotransduction pathways, mechano-epigenetic mechanisms, neural sensitization, and vascular factors, we propose that FHR may hypothetically partially normalize pathological fascial states by mechanically restoring tissue mobility and modifying stiffness-dependent signaling. Although direct molecular evidence of the effect of FHR in human fascia remains limited, this hypothesis provides a biologically plausible link between mechanical stress, ultrasound-visible structural alterations, and sustained clinical improvement. Full article

Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)—comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components—plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma–microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes—particularly CD8⁺ T cells, TFH cells, and B cells —are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies. Full article

High-frequency proton therapy shows promise for breast cancer (BC) treatment. We previously showed that BC cells’ metastatic potential (MP) correlates with their nanoparticle (NP) uptake efficiency. MP is known to be associated with microenvironment stiffness and radiosensitivity. Here, proton beam-irradiated MCF-7 and MDA-MB-231 cells were assessed for NP uptake efficiency under stiff (plastic) or soft (fibrin gel) conditions. In a stiff microenvironment, control MDA-MB-231 cells internalized 1.35-fold more NPs than MCF-7 (p < 0.0017), with comparably low uptake in soft conditions. After proton beam irradiation at a dose of 6 Gy, in stiff conditions, MDA-MB-231 cells showed a 1.6-fold increase in NP internalization compared to non-treated MDA-MB-231 (p < 0.0001), while MCF-7 cells showed no change, leading to an overall 1.86-fold difference between proton-treated MDA-MB-231 and MCF-7 cells (p < 0.0001). In soft conditions, irradiated MDA-MB-231 retained a 1.47-fold higher uptake of NPs than MCF-7 cells (p < 0.0172), but this value was 1.7-fold lower (p < 0.0001) compared to non-irradiated MDA-MB-231 cells on stiff plastic. Hence, therapeutic strategies combining proton irradiation with targeting tumor microenvironment softening may reduce post-irradiation metastasis risk. Full article

Human induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as powerful three-dimensional (3D) platforms for modeling human neurodevelopment and neurological disorders. However, the absence of a functional vascular network remains a critical limitation, restricting oxygen and nutrient delivery, impairing metabolic stability, and constraining long-term maturation. Conventional extracellular matrix (ECM) mimetics, such as Matrigel and other static synthetic hydrogels, provide biochemical support but fail to recapitulate the dynamic remodeling that characterizes the developing neurovascular niche. Recent advances in stimuli-responsive hydrogels offer spatiotemporal control over matrix stiffness, degradability, viscoelasticity, and biochemical cue presentation. In this review, we discuss dynamic hydrogel systems within a structure–property–function framework, highlighting how network chemistry and architecture may regulate endothelial sprouting, lumen formation, vascular stabilization, and neurovascular unit maturation in vascularized brain organoid models, based on evidence from both organoid studies and related biomaterial or vascular systems. Photoresponsive, enzyme-cleavable, thermo-responsive, supramolecular, bio-orthogonal click-based, and bioprinted platforms are discussed with emphasis on mechanotransduction, angiocrine signaling, and barrier specialization. Functional outcomes, including trans-endothelial electrical resistance, selective permeability, transporter expression, electrophysiological integration, and sustained perfusion, are discussed alongside translational challenges such as cytocompatibility, oxidative stress, scalability, and regulatory feasibility. Collectively, dynamic hydrogels provide a versatile biomaterial strategy for improving vascularization and aspects of functional maturation in brain organoid models with enhanced physiological relevance. Ultimately, stimuli-responsive hydrogel systems may serve as enabling platforms for engineering vascularized brain organoids and advancing human-relevant neurovascular disease modeling. Full article

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression. Full article

Mesenchymal stem cells (MSCs) sense biophysical cues from their microenvironment, which regulate cytoskeletal organization and the nuclear–cytoplasmic distribution of the mechanotransducer Yes-associated protein (YAP), thereby shaping cellular behavior. Prolonged ex vivo culture on non-physiologically rigid substrates induces persistent nuclear YAP localization, a phenomenon often referred to as mechanical memory. We therefore examined whether transient epigenetic modulation could modulate YAP subcellular localization in human bone marrow-derived MSCs. Treatment with the DNA methyltransferase inhibitor 5-azacitidine (5-Aza) shifted YAP localization toward the cytoplasm in MSCs, without overt changes in pluripotency marker expression or neural differentiation capacity. RNA sequencing revealed broad down-regulation of extracellular matrix (ECM)-related genes following 5-Aza treatment. Independent suppression of ECM production via TGF-β signaling similarly promoted cytoplasmic YAP localization. When subsequently transferred to soft substrates, 5-Aza–treated MSCs restored YAP relocalization despite prior expansion on stiff surfaces. Together, these findings suggest that transient 5-Aza treatment can partially alleviate mechanically induced YAP regulation associated with mechanical memory. Thus, simple and transient administration of 5-Aza may offer a practical means to improve the quality of MSCs during ex vivo expansion for cell-based therapies. Full article

Cardiac fibrosis represents a final common pathway in a wide range of cardiac disorders, leading to structural remodeling, diastolic dysfunction, and heart failure. From a pathologist’s viewpoint, fibrotic remodeling displays distinctive morphologic patterns such as interstitial, perivascular, and replacement fibrosis, which mirror specific cellular and molecular mechanisms. Central to this process is the activation of cardiac fibroblasts into myofibroblasts, driven by profibrotic signaling cascades such as transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog proteins (SMAD), Wingless/Integrated signaling pathway (Wnt)/βeta-catenin, and Hippo-Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathways. Neurohumoral mediators, including angiotensin II and aldosterone, further amplify extracellular matrix synthesis and tissue stiffness. Epigenetic modulators and non-coding RNAs (n-c RNAs) orchestrate transcriptional programs that perpetuate fibroblast activation. Histopathological correlates of these molecular events, collagen deposition, alpha-smooth muscle actin (α-SMA) expression, and extracellular matrix (ECM) cross-linking, can be demonstrated through immunohistochemistry and digital morphometry. This review integrates molecular signaling and morphologic evidence to delineate the mechanisms of cardiac fibrosis, emphasizing the pathologist’s role as a link between molecular insight and diagnostic interpretation. Understanding these intertwined processes provides the foundation for novel antifibrotic therapies targeting key molecular nodes of fibroblast activation and matrix remodeling. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a chief cause of cancer-related mortality throughout the world. SIRT6 is a fundamental sirtuin that governs several disease processes encompassing inflammation and cancer, including HCC. Longevity in centenarian Ashkenazi Jews was recently associated to novel allelic variants of SIRT6 (N308K/A313S), which ameliorate genome maintenance and DNA repair, and suppress cancer cells. It is currently unknown whether the above-mentioned SIRT6 variants display divergent or similar roles in HCC pathogenesis, compared to the wild-type (WT) counterpart. Methods: Our goal was to elucidate how these new centenarian-associated SIRT6 genetic variants may modulate HCC cell lines’ (HepG2 and Huh-7) aggressiveness and behavior, using functional and transcriptomic approaches. Results: We demonstrate that adeno-associated virus (AAV2/8)-mediated overexpression of centenarian-associated SIRT6 variants hampered HCC cell proliferation, with transcriptomic data showing the modulation of hallmark genes involved in the turnover of collagen/extracellular matrix (ECM). In addition, we found that AAV2/8-mediated overexpression of SIRT6 N308K/A313S decreased invasion and also increased stiffness in HCC cells, as measured by nanoindentation, in a more pronounced fashion compared to SIRT6 WT. Intracellular stiffness is a property of the cancer cells themselves, which, along with ECM invasiveness, plays a significant role in the progression of HCC. Conclusions: These data suggest that increased intracellular stiffening mirrors increased cell motility and invasive behavior; it can be indicative of suppressed cancer development and progression by the centenarian-associated SIRT6 N308K/A313S mutant. Full article

Despite significant progress in targeted cancer therapies and conventional imaging methodologies, the effective detection and treatment of solid tumours remain a major clinical challenge. This is thought to be caused by the complexity and heterogeneity found in the tumour microenvironment (TME), which significantly effects drug delivery and therapeutic response. Different levels of fibrosis, varying immune-cell infiltration, and disorganized vasculature form barriers for therapeutic approaches. However, in the next decade, radiotheranostics, defined here as the combined use of matched diagnostic and therapeutic radiopharmaceuticals, could present a targeted and flexible strategy for addressing some of the challenges caused by the TME. By combining molecular imaging with therapeutic delivery, it enables the in vivo visualization of TME features and the selective treatment of tumour and stromal compartments. This provides the unique opportunity to target tumour regions resistant to conventional therapies, including those shaped by (extracellular matrix) ECM stiffness, immune infiltration, or hypoxia. However, new strategies are needed to identify targets and evaluate their efficacy for more precise therapies. In this review, we will discuss why radiotheranostics is an ideal field for advancing the therapeutic approaches to solid tumours by incorporating the growing understanding of the TME. We will discuss how key microenvironmental features affect radiotracer distribution and treatment outcomes. We will highlight emerging tools including ECM- and immune-targeted imaging, patient-derived organoids, and organ-on-chip models which will be instrumental in developing physiologically relevant radiopharmaceutical therapies. Finally, we will discuss how spatial/single-cell transcriptomic approaches can support target discovery and allow for patient outcome assessment, with the aim of integrating microenvironment-aware insights into the development of novel radiotheranostic agents. Full article

Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), focal adhesion kinase (FAK) and the Hippo co-activators YAP1 and TAZ (WWTR1) promote proliferation, invasion, stemness and therapy resistance. Here, we synthesize evidence that quantitative changes in matrix stiffness remodel the miRNome and lncRNome in both tumor and stromal compartments, including extracellular vesicle cargo that reprograms metastatic niches. To address heterogeneity in experimental support, we classify mechanosensitive ncRNAs into studies directly validated by stiffness manipulation (e.g., tunable hydrogels/AFM) versus indirect associations based on mechanosensitive signaling, and we summarize physiological versus pathophysiological stiffness ranges across tissues discussed. We further review competing endogenous RNA (ceRNA) networks converging on mechanotransduction nodes and ECM remodeling enzymes, and discuss translational opportunities and challenges, including targeting mechanosensitive ncRNAs, combining ncRNA modulation with anti-stiffening strategies, delivery barriers in dense tumors, and the potential of circulating/exosomal ncRNAs as biomarkers. Overall, integrating ECM mechanics with ncRNA regulatory circuits provides a framework to identify feed-forward loops sustaining aggressive phenotypes in rigid microenvironments and highlights priorities for validation in physiologically relevant models. Full article

Pulmonary arterial hypertension (PAH) is marked by vascular remodeling, yet the role of adventitial fibrosis—and its modulation by sex and hormonal status—remains unclear. We examined stage-specific adventitial remodeling and pulmonary artery adventitial fibroblast (PAAF) mechanosensitivity in male, ovary-intact female, and ovariectomized (OVX) female Sprague–Dawley rats with SuHx-induced PAH. Hemodynamics, pulmonary artery histology, and adventitia-specific transcriptional profiling were integrated with in vitro assays of PAAFs exposed to defined substrate stiffness and stretch. All groups developed comparable increases in mean pulmonary arterial pressure, but vascular resistance shift and adventitial fibrosis diverged by sex: intact females showed attenuated increase in pulmonary vascular resistance and transient collagen accumulation, whereas OVX females mirrored the sustained, male-like progression. Extracellular matrix (ECM) gene activation occurred without smooth muscle actin induction, suggesting noncanonical fibrotic pathways. In vitro, intact female PAAFs required higher substrate stiffness to induce profibrotic gene expression, indicating a hormone-modulated stiffness threshold. OVX PAAFs showed persistent transcriptional reprogramming, while stretch-induced ECM upregulation occurred predominantly in male-derived PAAFs. These findings demonstrate that adventitial fibrosis in PAH is shaped by both hormonal and chromosomal sex, independent of hemodynamic severity, and highlight fibroblast mechanosensitivity as a potential target for stage- and sex-specific interventions. Full article

Metastasis accounts for most cancer-related deaths and hepatocellular carcinoma (HCC) is no exception. Midkine (MDK) is a multifunctional secreted protein elevated in HCC with a vague role in HCC. In this study, we used bioinformatics to verify MDK expression in HCC tumors, and next, we inhibited the MDK protein in invasive Hep3B cells using an MDK inhibitor (iMDK) both in vitro and in vivo. Our results showed that iMDK promoted cell migration and enhanced lamellipodia formation while at the same time downregulating the expression of cell–matrix adhesion genes. In order to also consider forces exerted by the surrounding matrix, we performed cell adhesion, transwell invasion, and 3D tumor spheroid invasion assays in two different stiffness conditions. Adhesion and invasion always exhibited opposite patterns, with adhesion being inhibited in soft matrix environments, accompanied by increased invasion, and a reverse effect in stiff environments. In vivo experiments where cells pre-treated with iMDK were implanted to zebrafish embryos showed overall reduced metastasis, verifying that MDK is a central mechanotransduction regulator that enables HCC cells to adapt their metastatic strategies to ECM stiffness. Thus, MDK inhibition effectively disrupts mechanosensitive coordination during metastasis, highlighting its potential as a therapeutic target. Full article

Breast cancer remains a leading cause of mortality among women worldwide. The inherent heterogeneity in tumors among patients with breast cancer poses a challenge to effective therapeutic management. The extracellular matrix (ECM) is an important structural component of the tumor microenvironment (TME) that regulates cellular behavior. When the ECM adopts a stiff configuration, this coincides with biochemical remodeling in response to biomechanical cues that drive tumor cell invasion, immune evasion, and metastatic spread in breast cancer. Emerging studies suggest that patient ancestry significantly impacts ECM stiffness to contribute to disparities in breast cancer survival. In this review, we discuss recent advances in our understanding of how the tumor ECM orchestrates breast cancer invasion and metastasis through mechanotransduction signaling to promote breast cancer progression. We also discuss ancestry-associated differences in breast ECM architecture and agents targeting mechanotransduction signaling pathways with potential to treat breast cancer and improve patient outcomes. Collectively, this review will highlight the significance of tumor mechanobiology and present emerging therapies that target stiffness-sensitive mechanotransduction pathways. By integrating mechanistic insights with therapeutic innovation, we aim to support the development of ECM-targeted therapies to enable more efficacious treatment of aggressive breast cancer subtypes. Full article

The evolving tumor microenvironment (TME) plays a critical role in breast cancer tumorigenesis, growth, and metastatic potential. This study focuses on two key components of the TME: tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR). We will analyze their multifaceted functions, emphasizing the significant mutual relationships among them, which dramatically affect disease outcomes and the effectiveness of treatments. TANs can either suppress or promote tumors, demonstrating notable functional flexibility in response to signals from their immediate environment. Concurrently, the proliferation of myofibroblasts and the extensive deposition of extracellular matrix (ECM), which characterize the DR, substantially alter the tumor’s physical properties, increasing its stiffness. This increased stiffness significantly obstructs immune system cells from accessing the tumor, ultimately limiting the effectiveness of therapies and contributing to a more clinically aggressive tumor behavior. A comprehensive understanding of the interactions among TANs, the desmoplastic stroma, and other elements of the TME is critical for developing new predictive biomarkers and establishing more effective targeted therapies. Full article