Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: March 11, 2023

The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation distant metastasis. Anticancer treatments including adjuvant therapies targeted are effective in eliminating cancer cells but limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role development through changes macromolecule components, degradation enzymes stiffness. These variations under control cellular components tissue via aberrant activation signaling pathways, interaction ECM to multiple surface receptors, mechanical impact. Additionally, shaped regulates immune which results suppressive microenvironment hinders efficacy immunotherapies. Thus, acts as barrier protect from supports progression. Nevertheless, profound regulatory network remodeling hampers design individualized antitumor treatment. Here, we elaborate on composition ECM, discuss specific mechanisms remodeling. Precisely, highlight impact development, proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, escape. Finally, emphasize "normalization" potential strategy for anti-malignant

Language: Английский

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Hypoxia-inducible factors: cancer progression and clinical translation

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(11)

Published: May 31, 2022

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each the 50 trillion cells in adult human body. Cancer co-opt this homeostatic system to drive cancer progression. HIFs activate transcription thousands genes mediate angiogenesis, stem cell specification, motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose lipid metabolism, immune evasion, invasion, metastasis. In Review, mechanisms consequences HIF activation presented. The current status future prospects small-molecule inhibitors use as therapeutics discussed.

Language: Английский

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Cancer-associated fibroblasts in the single-cell era

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(7), P. 793 - 807

Published: July 26, 2022

Language: Английский

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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 23(1), P. 146 - 146

Published: Dec. 23, 2021

Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, turnover by degrading extracellular (ECM) components releasing matrikines, surface-bound cytokines, growth factors, or their receptors. Among MMPs, MMP-14 is driving force behind destruction during cancer invasion metastasis. also influences both intercellular as well cell-matrix communication regulating many plasma membrane-anchored proteins. cells other stroma, embedded in a common matrix, interact means various adhesive structures, particularly invadopodia are capable to remodel through spatially temporally finely tuned proteolysis. As deeper understanding underlying functional mechanisms beneficial for development new prognostic predictive markers targeted therapies, this review examined current knowledge interplay MMPs context protein, subcellular, cellular level focus MMP14.

Language: Английский

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Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(3), P. 714 - 770

Published: June 23, 2022

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, metalloproteinases are proteases capable remodeling extracellular matrix. More recently, MMPs have been demonstrated play numerous additional biologic roles cell signaling, immune regulation, and transcriptional control, all which unrelated degradation In this review, we will present milestones major discoveries MMP research, including various clinical trials for use inhibitors. We discuss reasons behind failures most inhibitors treatment cancer inflammatory diseases. There still misconceptions about pathophysiological best strategies inhibit detrimental functions. This review aims preclinical models human pathologies. new biochemical tools track proteolytic activity vivo ex vivo, addition future pharmacological alternatives functions

Significance Statement

Matrix (MMPs) implicated inflammatory, autoimmune, cancers, pathogen-mediated Initially overlooked, contributions can be both beneficial disease progression resolution. Thousands substrates suggested, few hundred validated. After more than 60 years there remain intriguing enigmas solve regarding biological

Language: Английский

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Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Nature, Journal Year: 2021, Volume and Issue: 599(7886), P. 673 - 678

Published: Nov. 3, 2021

Language: Английский

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Targeting the tumor stroma for cancer therapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Nov. 2, 2022

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part the tumor microenvironment, stroma is highly dynamic, heterogeneous commonly tumor-type specific, it mainly includes noncellular compositions such as extracellular matrix unique cancer-associated vascular system well a wide variety cellular components including activated fibroblasts, mesenchymal cells, pericytes. All these elements operate with each other in coordinated fashion collectively promote initiation, progression, metastasis therapeutic resistance. Over past few decades, numerous studies have been conducted to study interaction crosstalk between neoplastic cells. Meanwhile, we also witnessed exponential increase investigation recognition critical roles solid tumors. A series clinical trials targeting launched continually. In this review, introduce discuss current advances understanding various their cancers. We elaborate on potential novel approaches for tumor-stroma-based targeting, aim leap from bench bedside.

Language: Английский

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Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 6, 2022

The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays crucial role shaping their progression. Many desmoplastic including breast cancer involve significant accumulation type I collagen. However, recently it has become clear precise distribution organisation molecules such as collagen equally important abundance. Cancer-associated fibroblasts (CAFs) coexist within tissues play both pro- anti-tumourigenic roles through remodelling ECM. Here, using temporal proteomic profiling decellularized tumours, we interrogate evolving matrisome during We identify 4 key matrisomal clusters, pinpoint XII critical component regulates organisation. Through combining our proteomics with single-cell transcriptomics, genetic manipulation models, show how CAF-secreted alters to create pro-invasive microenvironment supporting metastatic dissemination. Finally, patient cohorts may represent an indicator patients at high risk relapse.

Language: Английский

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Cell–3D matrix interactions: recent advances and opportunities

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 32(10), P. 883 - 895

Published: April 8, 2022

The diversity of hundreds extracellular matrix (ECM) molecules in different tissues and their interactions are now being documented 'matrisome' databases.Physical properties the 3D ECM, including viscoelasticity microarchitecture, can govern cell adhesion, mechanotransduction, multiple modes migration.New advances ECM biology identifying mechanisms cancer progression fibrosis, as well potential therapeutic targets.Characterizations cell–ECM feedback loops computational modeling providing new insights opportunities for intervention diseases disorders. Tissues consist cells surrounding (ECM). Cell–ECM play crucial roles embryonic development, differentiation, tissue remodeling, fibrosis cancer. Recent research characterizing cell–matrix include detailed descriptions associated molecules, complex intermolecular development disease, identification distinctive migration ECMs, into organ formation. Exploring physical features microenvironments bidirectional regulation signaling organization emphasize dynamic nature these interactions, which that exacerbate disease. Understanding potentially lead to targeted interventions. New on interactionsThe with (see Glossary) during formation adult homeostasis, pathogenesis such This field has expanded explosively after discovery many surface receptors. Our goal this brief review is highlight recent conceptual experimental should provide exciting future cell–3D interactions.Diversity interactionsA starting ~2019 been widespread adoption term – is, comprising it changes disease pathogenesis. holistic concept matrisomes moves beyond classical studies focusing a single protein or family not only structural proteins, collagens, elastin, proteoglycans, fibronectin, but also matrix-associated enzymes inhibitors, matrix-bound growth factors, some cases receptors [1.Karamanos N.K. et al.A guide composition functions matrix.FEBS J. 2021; 288: 6850-6912Crossref PubMed Scopus (65) Google Scholar,2.Izzi V. al.Pan-cancer analysis genomic alterations mutations matrisome.Cancers (Basel). 2020; 12: 2046Crossref (27) Scholar]. Among examples, have used matrisome analyses characterize basement membranes (https://bmbase.manchester.ac.uk/), discover ECM-associated genes more than other [2.Izzi Scholar], identify thrombospondin tenascin links collagen alignment breast [3.Tomko L.A. al.Targeted identifies thrombospondin-2 tenascin-C aligned stroma from invasive carcinoma.Sci. Rep. 2018; 8: 12941Crossref (37) bioengineered models human pancreatic [4.Osuna de la Pena D. al.Bioengineered recapitulate vivo tumour biology.Nat. Commun. 5623Crossref (11) Scholar].Many publications still at descriptive level. There considerable overlaps between components 'adhesome,' comprises adhesions, especially focal adhesions (e.g., see www.adhesome.org). Both 'omics' approaches major applying increasingly sophisticated methods understand involving networks rather just few selected proteins past. Unexpected findings may arise terms groups regulating components. Exemplifying crosstalk, planar membrane two its biochemically unrelated constituents, laminin IV, strongly regulate assembly fibrillar component, variety types [5.Lu al.Basement regulates fibronectin using sliding driven by contractile winch.Dev. Cell. 52: 631-646 e634Abstract Full Text PDF (24) Scholar].We know vary widely depending type biochemical mechanical (Figure 1). Multiple characterized recently range lamellipodial characteristic mesenchymal fibroblast-like rounded amoeboid immune certain [6.Bodor D.L. al.Of shapes motion: basis animal migration.Dev. 550-562Abstract (45) Scholar,7.Yamada K.M. Sixt M. Mechanisms migration.Nat. Rev. Mol. Cell Biol. 2019; 20: 738-752Crossref (262) lobopodial cross-linked linearly elastic spatially confined intracellular pressure, cortical actin flow, ion fluxes, [8.Zhao R. al.Cell sensing decision-making confinement: role TRPM7 tug war hydraulic pressure cross-sectional area.Sci. Adv. 5eaaw7243Crossref (35) Scholar, 9.Patel S. al.Myosin II Arp2/3 cross-talk governs lamellipodia formation.Mol. 32: 579-589Crossref 10.Ullo M.F. Logue J.S. ADF cofilin-1 collaborate promote flow leader bleb-based cells.eLife. 10e67856Crossref (6) 11.Reversat A. al.Cellular locomotion environmental topography.Nature. 582: 582-585Crossref (69) 12.Yolland L. al.Persistent polarized global essential directionality 21: 1370-1381Crossref (22) Scholar].The microarchitecture affect differentiation [13.Doyle A.D. al.Local microenvironment through spatiotemporal dynamics contractility-dependent adhesions.Nat. 2015; 6: 8720Crossref (268) Scholar,14.Seo B.R. al.Collagen mechanically controls myofibroblast differentiation.Proc. Natl. Acad. Sci. U. 117: 11387-11398Crossref (58) For example, networks, fiber thickness pore size, adipose stromal toward process independent overall stiffness previously known stem [14.Seo Scholar,15.Chaudhuri O. al.Effects cellular behaviour.Nature. 584: 535-546Crossref (427) Scholar].Matrix propertiesThe local migratory speed show differences molecular elasticity [15.Chaudhuri Examining whether an soft stiff numerous previous [16.Hayward M.K. al.Tissue mechanics fate, cancer.Dev. 56: 1833-1847Abstract (20) Scholar,17.Xue B. al.Engineering hydrogels homogeneous controlling lineage specification.Proc. 118e2110961118Crossref (13) Scholar] ideally be complemented behavior environments differing viscoelasticity. reason biological matrices often viscoelastic, they display combination viscosity thick fluid attempts return material original form deforming force released. results plastic deformation slipping, creep 'stress relaxation' response deformed, without returning form. Viscoelasticity modulated extent crosslinking property effects behavior, although underlying yet clear. altered rheology filopodial versus protrusions leading edge cell, rates spreading migration, processes morphogenesis, epithelial-mesenchymal transition, invasion, [18.Adebowale K. al.Enhanced substrate stress relaxation promotes filopodia-mediated Mater. 1290-1299Crossref (36) 19.Gong Z. al.Matching timescales maximizes viscoelastic substrates.Proc. 115: E2686-E2695Crossref (129) 20.Wisdom al.Matrix plasticity confining microenvironments.Nat. 9: 4144Crossref (162) 21.Yang mechanosensing synthetic controlled biophysical dynamics.Nat. 3514Crossref 22.Indana al.Viscoelasticity adhesion biomaterials control pluripotent morphogenesis culture.Adv. 33e2101966Crossref (17) 23.Chang A.C. al.Precise tuning characterization interfaces study early transition behaviors.Langmuir. 2022; (Published online February 10, 2022)https://doi.org/10.1021/acs.langmuir.1c03048Crossref (3) 24.Hui E. al.The combined influence adhesive cues fibroblast organization.Cell. Bioeng. 14: 427-440Crossref (9) fact chemical substantially alter mode, speed, means one cannot simply 'work 3D' due factors An ongoing challenge will generate accurately mimic specific use ex tissues. Development physiological simple gels current valuable accurate platforms testing translational approaches.MechanotransductionDifferent elicit distinct responses cells. 2D revealed test repetitively probing [25.Plotnikov S.V. al.Force fluctuations within mediate ECM-rigidity directed migration.Cell. 2012; 151: 1513-1527Abstract (559) analogous hikers footing when crossing unstable terrain. Cells sense respond ECM-transmitted forces tension involves integrin-based where actomyosin-mediated transmitted substrata [26.Zuidema al.Crosstalk complexes mechanotransduction.Bioessays. 42e2000119Crossref (31) Scholar,27.Doyle al.Cell-extracellular dynamics.Phys. 19https://doi.org/10.1088/1478-3975/ac4390Crossref (8) In environments, mechanotransduction level resembles under conditions stiffer substrates stabilize while softer, flexible shorter lifetimes faster Scholar].Mechanotransduction becomes particularly concerning cycle. evidence fibroblasts migrating reveals prior translocation, initially deform (prestrain) fibrils, increasing self-generated contracting transmitting essentially first 'pulling up slack rope' (i.e., fibrils [28.Doyle al.3D anterior contraction generates prestrain.Dev. 826-841.e4Abstract Scholar]). Interestingly, epithelial relatively equal-and-opposite strain transmission posterior directions 2A ) [29.Hall M.S. al.Fibrous nonlinear enables positive ECMs.Proc. 2016; 113: 14043-14048Crossref (174) (nonepithelial) cancers constant prestrains twofold greater front rear suggesting disconnect propagation 2A) prestrain likely genetically primed contractility-centric mode higher expression myosin II) enhanced microenvironment. sequence events distinctive, actomyosin contractions preceding leading-edge protrusive activity, helps establish unique cycle 2B–C) Discrepancies cycles importance conditions.Figure 2Mechanotransduction migration.Show full caption(A) Schematic showing directionally gels. Mesenchymal (left) high extensive integrin ligation large strains larger rear. Similar attributes seen fibrosarcoma cells, majority (right) smaller, transient rear, lower graph summarizing latter concept, requires further testing). (B C) schematic shows matrix. Yellow arrows depict directional applied matrix, magenta indicate relative summed given region. During cycle, (C) retrograde pull stabilizes (gray ovals) edge. A contralateral anterograde (increased direction migration) leads pinching followed increase protrusion (broken white line). Abbreviation: matrix.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition, (elastic etc.) alters mechanotransduction. suggest ECMs Viscoelastic effective eliciting compared Future evaluate interacting properties, vitro microenvironments.The nucleus migrationSome 'nuclear piston' pulled anteriorly contractility pressurize drive 'lobopodial' forward [30.Petrie R.J. al.Activating nuclear piston mechanism tumor cells.J. 2017; 216: 93-100Crossref (63) (plastic), mechanosensitive channels generated elevated hydrostatic triggering channel activation; resulting influx sodium calcium ions enhances osmotic provides additional extending promoting efficient [31.Lee H.P. activates paths microenvironments.Sci. 7eabd4058Google Scholar].Another intriguing finding stiff, bulky ruler help choice wider, readily traversed passageway [32.Renkawitz al.Nuclear positioning facilitates along path least resistance.Nature. 568: 546-550Crossref (125) Scholar,33.Lomakin A.J. acts tailoring spatial constraints.Science. 370eaba2894Crossref (110) Besides serving ruler, conjunction cytoskeleton function, gauge activate epigenetic pathways 3) Scholar,34.Venturini measures shape proprioception behavior.Science. 370eaba2644Crossref (102) 35.Maurer Lammerding driving force: disease.Annu. Biomed. Eng. 443-468Crossref (80) 36.Alisafaei F. al.Regulation architecture, mechanics, nucleocytoplasmic shuttling geometric constraints.Proc. 116: 13200-13209Crossref (82) Scholar].Figure 3Multiple mechanosensing, mechanotransduction.Show captionThe nucleus, largest organelle, function entry narrow spaces channels. contraction, thereby termed lobopodia. serve sensor responding confinement. Finally, signal transducer initiating gene expression.View (PPT)Cancer dynamicsCancer invasion continues another very active investigation various ECM. Before malignant invade interstitial tissues, must usually breach barrier surrounds 4). Although proteases degrade protease-independent breaching occur. Physical extension penetrate expand holes ATP production Caenorhabditis elegans [37.Kelley L.C. al.Adaptive F-actin polymerization localized absence MMPs.Dev. 48: 313-328.e8Abstract Human nonproteolytic repetitive microspikes widen filopodia enlarging perforations; protruding subsequently probe [38.Chang Chaudhuri Beyond proteases: invasion.J. 218: 2456-2469Crossref 39.Eschenbruch al.From fibers: remodeling acini drives II-mediated invasion.Cells. 10: 1979Crossref 40.Gong al.Recursive dissipation chemo-mechanical oscillatory invadopodia.Cell 35109047Abstract Cellular metabolic activation important successful crosstalk Scholar,41.Zanotelli M.R. al.Mechanoresponsive metabolism metastasis.Cell Metab. 33: 1307-1321Abstract 42.Romani P. metabolism.Nat. 22: 22-38Crossref (94) 43.Torrino al.Mechano-induced microtubule glutamylation 1342-1357.e10Abstract (18) 4Different membrane.Show captionCancer transiently barriers mechanisms. proteases, metalloproteinases (MMPs), locally, MMPs tips invadopodia. Even if inhibited, tiny perforations requiring energy (orange shading) (yellow arrows) push laterally ridge around expanding hole (red mounds). both processes, proteolysis perforations.View (PPT)Although generation thought involve contractility, relationship levels nonmuscle invasiveness complex. Some isoforms actomyosin-associated predicted facilitate others decreased consistent suppressor Scholar,44.Parajon mechanobiome: goldmine therapeutics.Am. Physiol. 320: C306-C323Crossref Scholar,45.Picariello H.S. IIA suppresses glioblastoma sensitive manner.Proc. 15550-15559Crossref (25) bifunctional complexity myosin-X enhancing suppressing modulating [46.Peuhu al.Myosin-X-dependent limits invasion.bioRxiv. October 22, 2021)https://doi.org/10.1101/2021.10.22.464987Google Scholar].Although obvious source disrupting structure breaching, contributor lateral branches density [47.Papalazarou Maches

Language: Английский

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Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 7, 2022

Abstract Intratumor heterogeneity may result from the evolution of tumor cells and their continuous interactions with microenvironment which collectively drives tumorigenesis. However, an appearance cellular molecular creates a challenge to define features linked malignancy. Here we perform multiregional single-cell RNA sequencing (scRNA-seq) analysis seven liver cancer patients (four hepatocellular carcinoma, HCC three intrahepatic cholangiocarcinoma, iCCA). We identify dynamics malignant communication networks tumor-associated immune cells, are validated using additional scRNA-seq data 25 12 iCCA as stable fingerprint embedded in ecosystem representing aggressiveness. further validate top ligand-receptor interaction pairs (i.e., LGALS9-SLC1A5 SPP1-PTGER4 between macrophages) associated unique transcriptome 542 patients. Our study unveils ecosystems, open path for therapeutic exploration.

Language: Английский

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