Tumor-associated fibrosis impairs the response to immunotherapy

Matrix Biology, Год журнала: 2023, Номер 119, С. 125 - 140

Опубликована: Апрель 18, 2023

Язык: Английский

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1H-detected characterization of carbon–carbon networks in highly flexible protonated biomolecules using MAS NMR

Journal of Biomolecular NMR, Год журнала: 2023, Номер 77(3), С. 111 - 119

Опубликована: Июнь 1, 2023

Abstract In the last three decades, scope of solid-state NMR has expanded to exploring complex biomolecules, from large protein assemblies intact cells at atomic-level resolution. This diversity in macromolecules frequently features highly flexible components whose insoluble environment precludes use solution study their structure and interactions. While High-resolution Magic-Angle Spinning (HR-MAS) probes offer capacity for gradient-based 1 H-detected spectroscopy solids, such are not commonly used routine MAS experiments. As a result, most exploration regime entails either 13 C-detected experiments, partially perdeuterated systems, or ultra-fast MAS. Here we explore proton-detected pulse schemes probing through-bond C– C networks mobile sidechains as well polysaccharides broadband manner. We demonstrate mixture microtubule-associated (MAP) tau human microtubules (MTs), cell wall fungus Schizophyllum commune using 2D 3D spectroscopy, show its viability obtaining unambiguous correlations standard fast-spinning high ultra-high magnetic fields.

Язык: Английский

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Osteopontin is a therapeutic target that drives breast cancer recurrence

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 24, 2024

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of recurrence. Osteopontin promotes cell proliferation, recruits macrophages, synergizes with IL-4 further polarize them into a pro-tumorigenic state. Macrophage depletion inhibition decrease recurrent growth. Furthermore, targeting primary tumor-bearing female mice prevents metastasis, permits T infiltration activation, improves anti-PD-1 immunotherapy response. Clinically, expression is higher metastatic tumors versus patient-matched tumors. positively correlates macrophage infiltration, increases grade, its elevated pathway activity associated poor prognosis Our findings suggest clinical implications alternative therapeutic strategy based on osteopontin's multiaxial role progression

Язык: Английский

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Enhanced Tumor Site Accumulation and Therapeutic Efficacy of Extracellular Matrix‐Drug Conjugates Targeting Tumor Cells

Small, Год журнала: 2024, Номер unknown

Опубликована: Июнь 3, 2024

Abstract The extracellular matrix (ECM) engages in regulatory interactions with cell surface receptors through its constituent proteins and polysaccharides. Therefore, nano‐sized conjugated doxorubicin (DOX) is utilized to produce matrix‐drug conjugates (ECM‐DOX) tailored for targeted delivery cancer cells. ECM‐DOX nanoparticles exhibit rod‐like morphology, boasting a commendable drug loading capacity of 4.58%, coupled acid‐sensitive release characteristics. Notably, enhance the uptake by tumor cells possess ability penetrate endothelial infiltrate multicellular spheroids. Mechanistic insights reveal that internalization nanoparticle facilitated clathrin‐mediated endocytosis macropinocytosis, intricately involving hyaluronic acid integrins. Pharmacokinetic assessments unveil prolonged blood half‐life at 3.65 h, substantial improvement over 1.09 h observed free DOX. A sustained accumulation effect sites, levels tissues surpassing those DOX several‐fold. profound therapeutic impact evident their notable inhibition growth, extension median survival time animals, significant reduction DOX‐induced cardiotoxicity. ECM platform emerges as promising carrier avant‐garde nanomedicines realm treatment.

Язык: Английский

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The role of the hypothalamic–pituitary–thyroid axis in thyroid cancer

The Lancet Diabetes & Endocrinology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Novel transcripts of EMT driving the malignant transformation of oral submucous fibrosis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 26, 2025

Abstract Oral submucous fibrosis (OSF) is a chronic, progressive, and fibrotic condition of the oral mucosa that carries an elevated risk malignant transformation. We aimed to identify validate novel genes associated with regulation epithelial-to-mesenchymal transition (EMT) in OSF. Genes regulating EMT were identified through differential gene expression analysis, using LogFC threshold -1 + 1 padj value < 0.05, based on data from GEO datasets TCGA-HNSC datasets. The curated correlated functional cancer states subjected clustering candidate genes. Integration bioinformatics proteomics led discovery MMP9 , SPARC ITGA5 as candidates. Comprehensive pathway immunohistochemical analyses confirmed their roles OSF, squamous cell carcinoma (OSCC), OSF-associated (OSFSCC). significant malignancy suggest mechanism which fibrosis-associated type 2 undergoes 3 EMT, driving OSF towards malignancy.

Язык: Английский

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A Review of Talin- and Integrin-Dependent Molecular Mechanisms in Cancer Invasion and Metastasis

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1798 - 1798

Опубликована: Фев. 20, 2025

Cancer is the second most common cause of death in world, representing one main economic burdens health care and research. The effort research has mainly focused on limiting growth a localized tumor, but recently, there been more attention restricting spreading cancer via invasion metastasis. signaling pathways behind these two processes share many molecules with physiological regulating cell adhesion migration, and, moreover, migration themselves underlie tumor potential for invasion. In this work, we reviewed latest literature about development their regulation by migration- adhesion-related proteins, specific focus talins integrins. We also summarized recent developments approaches to anti-cancer therapies, concentrating migration-related therapies.

Язык: Английский

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The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 18, 2025

The mechanical properties of the tumor microenvironment (TME) undergo significant changes during growth, primarily driven by alterations in extracellular (ECM) stiffness and viscoelasticity. These not only promote progression but also hinder therapeutic efficacy impairing drug delivery activating mechanotransduction pathways that regulate crucial cellular processes such as migration, proliferation, resistance to therapy. In this review, we examine mechanisms through which cells sense transmit signals maintain homeostasis biomechanically altered TME. We explore current computational modelling strategies for pathways, highlighting need developing models incorporate additional components mechanosignaling machinery. Furthermore, review available methods measuring tumors clinical settings aiming at restoring TME blocking deregulated pathways. Finally, propose proper characterization a deeper understanding landscape TME, both tissue levels, are essential account influence forces on treatment efficacy.

Язык: Английский

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Osteopontin in Cancer: Mechanisms and Therapeutic Targets

International Journal of Translational Medicine, Год журнала: 2022, Номер 2(3), С. 419 - 447

Опубликована: Авг. 19, 2022

Despite significant advances in the understanding of cancer biology, is still a leading cause death worldwide. Expression tumor microenvironment component, osteopontin, tissues, plasma, and serum, has been shown to be associated with poor prognosis survival rate various human cancers. Recent studies suggest that osteopontin drives development aggressiveness using strategies. In this review, we first provide an overview how promotes progression, such as growth, invasion, angiogenesis, immune modulation, well metastasis chemoresistance. Next, address functional activities are modulated by interaction integrins CD44 receptors, but also post-translational modification, proteolytic processing several proteases, phosphorylation, glycosylation. Then, review activates tumor-associated macrophages (TAMs) cancer-associated fibroblasts (CAFs), functions immunosuppressor regulating surveillance checkpoint microenvironment. Finally, discuss potential applications biomarker therapeutic target.

Язык: Английский

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Ablation of integrin-mediated cell–collagen communication alleviates fibrosis

Annals of the Rheumatic Diseases, Год журнала: 2023, Номер 82(11), С. 1474 - 1486

Опубликована: Июль 21, 2023

Activation of fibroblasts is a hallmark fibrotic processes. Besides cytokines and growth factors, are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical mechanical signals enabling cells to mount appropriate responses according biological demands. The aim this work was investigate in vivo role collagen-fibroblast interactions for regulating fibroblast functions fibrosis.Triple knockout (tKO) mice with combined ablation integrins α1β1, α2β1 α11β1 were created address significance integrin-mediated cell-collagen communication. Properties primary dermal lacking collagen-binding delineated vitro. Response tKO skin bleomycin induced challenge assessed.Triple integrin-deficient develop normally, transiently smaller reveal mild alterations mechanoresilience skin. Fibroblasts from these culture show defects cytoskeletal architecture, traction stress generation, production organisation. Ablation three leads increased levels discoidin domain receptor 2, an alternative recognising collagens However, overexpression fails compensate adhesion spreading on collagen substrates Mice severely attenuated response impaired mechanotransduction, reduced organisation.The data provide evidence crucial force generation differentiation vitro deposition tissue remodelling vivo. Targeting fibroblast-collagen might represent promising therapeutic approach regulate connective diseases.

Язык: Английский

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