Extracellular Matrix Signaling Cues: Biological Functions, Diseases, and Therapeutic Targets

Abstract

Extracellular matrix (ECM) is a dynamic, three-dimensional network that provides structural support and regulates key biological processes, including cell adhesion, migration, differentiation, and signal transduction. Its mechanical properties, such as stiffness, topology, and viscoelasticity, are crucial in normal and pathological conditions, influencing cell behavior through mechanotransduction pathways. Dysregulation of ECM is linked to various diseases, making a thorough understanding of its composition and properties essential. This review discusses ECM composition, physical properties, and the limitations of in vitro ECM models. It highlights the role of ECM in tissue homeostasis, particularly in regulating cell behavior via mechanotransduction, focusing on force-sensitive sensors like integrins, Piezo1, TRPV4, and YAP/TAZ. Additionally, the review explores ECM remodeling in cancer, fibrosis, and cardiovascular diseases, along with current therapeutic strategies targeting ECM components, such as nanotechnology-based therapies, small molecule inhibitors, and CAF-targeted therapies. Challenges and clinical applications of these therapies are also discussed. Finally, the review looks ahead to future research, emphasizing the integration of ECM-targeted therapies in precision medicine and novel approaches to normalizing ECM composition and structure for therapeutic benefits. This review provides mechanobiological insights into therapeutic strategies targeting the ECM.

Keywords

ECM dysregulation / ECM remodeling / ECM targeted therapies / extracellular matrix (ECM) / mechanotransduction

References

[1] D. Pally and A. Naba, “Extracellular Matrix Dynamics: A Key Regulator of Cell Migration Across Length-Scales and Systems,” Current Opinion in Cell Biology 86 (2024): 102309.

[2] N. Karamanos, S. Ricard-Blum, and D. Kletsas, “Extracellular Matrix: The Dynamic Structural and Functional Network in Health and Disease,” IUBMB Life 74, no. 10 (2022): 926.

[3] Y. Fu, Y. Zhou, K. Wang, et al., “Extracellular Matrix Interactome in Modulating Vascular Homeostasis and Remodeling,” Circulation Research 134, no. 7 (2024): 931-949.

[4] C. T. Mierke, “Extracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells,” Cells 13, no. 1 (2024): 96.

[5] A. Valdivia, A. M. Avalos, and L. Leyton, “Thy-1 (CD90)-Regulated Cell Adhesion and Migration of Mesenchymal Cells: Insights Into Adhesomes, Mechanical Forces, and Signaling Pathways,” Frontiers in Cell and Developmental Biology 11 (2023): 1221306.

[6] N. V. Popova and M. Jucker, “The Functional Role of Extracellular Matrix Proteins in Cancer,” Cancers (Basel) 14, no. 1 (2022): 238.

[7] W. Xie, X. Wei, H. Kang, et al., “Static and Dynamic: Evolving Biomaterial Mechanical Properties to Control Cellular Mechanotransduction,” Advanced Science (Weinh) 10, no. 9 (2023): e2204594.

[8] T. Guo, C. He, A. Venado, et al., “Extracellular Matrix Stiffness in Lung Health and Disease,” Comprehensive Physiology 12, no. 3 (2022): 3523-3558.

[9] G. Tian and T. Ren, “Mechanical Stress Regulates the Mechanotransduction and Metabolism of Cardiac Fibroblasts in Fibrotic Cardiac Diseases,” European Journal of Cell Biology 102, no. 2 (2023): 151288.

[10] J. Vasudevan, K. Jiang, J. G. Fernandez, et al., “Extracellular Matrix Mechanobiology in Cancer Cell Migration,” Acta Biomaterialia 163 (2023): 351-364.

[11] G. Guerrero-Barbera, N. Burday, and M. Costell, “Shaping Oncogenic Microenvironments: Contribution of Fibronectin,” Frontiers in Cell and Developmental Biology 12 (2024): 1363004.

[12] C. A. Horta, K. Doan, and J. Yang, “Mechanotransduction Pathways in Regulating Epithelial-Mesenchymal Plasticity,” Current Opinion in Cell Biology 85 (2023): 102245.

[13] K. Wang, D. Wen, X. Xu, et al., “Extracellular Matrix Stiffness-The Central Cue for Skin Fibrosis,” Frontiers in Molecular Biosciences 10 (2023): 1132353.

[14] M. Hu and L. Huang, “Strategies Targeting Tumor Immune and Stromal Microenvironment and Their Clinical Relevance,” Advanced Drug Delivery Reviews 183 (2022): 114137.

[15] R. Rimal, P. Desai, R. Daware, et al., “Cancer-Associated Fibroblasts: Origin, Function, Imaging, and Therapeutic Targeting,” Advanced Drug Delivery Reviews 189 (2022): 114504.

[16] H. Zhang, X. Yue, Z. Chen, et al., “Define Cancer-Associated Fibroblasts (CAFs) in the Tumor Microenvironment: New Opportunities in Cancer Immunotherapy and Advances in Clinical Trials,” Molecular Cancer 22, no. 1 (2023): 159.

[17] Y. Zhang, Z. Fang, D. Pan, et al., “Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response,” Advanced Materials 36, no. 25 (2024): e2401304.

[18] Q. Qin, R. Yu, J. E. Eriksson, et al., “Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Therapy: Challenges and Opportunities,” Cancer Letters 591 (2024): 216859.

[19] B. Toledo, M. Picon-Ruiz, J. A. Marchal, et al., “Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives,” International Journal of Molecular Sciences 23, no. 24 (2022): 15576.

[20] A. D. Theocharis, S. S. Skandalis, C. Gialeli, et al., “Extracellular Matrix Structure,” Advanced Drug Delivery Reviews 97 (2016): 4-27.

[21] J. H. Longstreth and K. Wang, “The Role of Fibronectin in Mediating Cell Migration,” American Journal of Physiology. Cell Physiology 326, no. 4 (2024): C1212-C1225.

[22] N. K. Karamanos, A. D. Theocharis, Z. Piperigkou, et al., “A Guide to the Composition and Functions of the Extracellular Matrix,” The FEBS Journal 288, no. 24 (2021): 6850-6912.

[23] F. E. Uhl, F. Zhang, R. A. Pouliot, et al., “Functional Role of Glycosaminoglycans in Decellularized Lung Extracellular Matrix,” Acta Biomaterialia 102 (2020): 231-246.

[24] X. Zhang and J. Weickenmeier, “Brain Stiffness Follows Cuprizone-Induced Variations in Local Myelin Content,” Acta Biomaterialia 170 (2023): 507-518.

[25] J. Weickenmeier, R. de Rooij, S. Budday, et al., “Brain Stiffness Increases With Myelin Content,” Acta Biomaterialia 42 (2016): 265-272.

[26] A. J. Engler, S. Sen, H. L. Sweeney, et al., “Matrix Elasticity Directs Stem Cell Lineage Specification,” Cell 126, no. 4 (2006): 677-689.

[27] V. Mieulet, C. Garnier, Y. Kieffer, et al., “Stiffness Increases With Myofibroblast Content and Collagen Density in Mesenchymal High Grade Serous Ovarian Cancer,” Scientific Reports 11, no. 1 (2021): 4219.

[28] A. Wieland, P. L. Strissel, H. Schorle, et al., “Brain and Breast Cancer Cells With PTEN Loss of Function Reveal Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Utilizing 3D Scaffolds and Aligned Microfiber Tracts,” Cancers (Basel) 13, no. 20 (2021): 5144.

[29] A. J. Booth, R. Hadley, A. M. Cornett, et al., “Acellular Normal and Fibrotic Human Lung Matrices as a Culture System for in Vitro Investigation,” American Journal of Respiratory and Critical Care Medicine 186, no. 9 (2012): 866-876.

[30] S. Safaei, R. Sajed, A. Shariftabrizi, et al., “Tumor Matrix Stiffness Provides Fertile Soil for Cancer Stem Cells,” Cancer Cell International 23, no. 1 (2023): 143.

[31] H. Du, J. M. Bartleson, S. Butenko, et al., “Tuning Immunity Through Tissue Mechanotransduction,” Nature Reviews Immunology 23, no. 3 (2023): 174-188.

[32] I. Acerbi, L. Cassereau, I. Dean, et al., “Human Breast Cancer Invasion and Aggression Correlates With ECM Stiffening and Immune Cell Infiltration,” Integrative Biology (Camb) 7, no. 10 (2015): 1120-1134.

[33] J. L. Leight, M. A. Wozniak, S. Chen, et al., “Matrix Rigidity Regulates a Switch Between TGF-beta1-Induced Apoptosis and Epithelial-Mesenchymal Transition,” Molecular Biology of the Cell 23, no. 5 (2012): 781-791.

[34] J. J. Northey, A. S. Barrett, I. Acerbi, et al., “Stiff Stroma Increases Breast Cancer Risk by Inducing the Oncogene ZNF217,” Journal of Clinical Investigation 130, no. 11 (2020): 5721-5737.

[35] J. Schrader, T. T. Gordon-Walker, R. L. Aucott, et al., “Matrix Stiffness Modulates Proliferation, Chemotherapeutic Response, and Dormancy in Hepatocellular Carcinoma Cells,” Hepatology 53, no. 4 (2011): 1192-1205.

[36] J. Lee, S. Condello, B. Yakubov, et al., “Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression,” Clinical Cancer Research 21, no. 19 (2015): 4482-4493.

[37] S. C. Wei, L. Fattet, J. H. Tsai, et al., “Matrix Stiffness Drives Epithelial-Mesenchymal Transition and Tumour Metastasis Through a TWIST1-G3BP2 Mechanotransduction Pathway,” Nature Cell Biology 17, no. 5 (2015): 678-688.

[38] L. Fattet, H. Y. Jung, M. W. Matsumoto, et al., “Matrix Rigidity Controls Epithelial-Mesenchymal Plasticity and Tumor Metastasis via a Mechanoresponsive EPHA2/LYN Complex,” Developmental Cell 54, no. 3 (2020): 302-316.e307.

[39] Z. Mai, Y. Lin, P. Lin, et al., “Modulating Extracellular Matrix Stiffness: A Strategic Approach to Boost Cancer Immunotherapy,” Cell Death & Disease 15, no. 5 (2024): 307.

[40] S. Choi, M. A. Whitman, A. A. Shimpi, et al., “Bone-Matrix Mineralization Dampens Integrin-Mediated Mechanosignalling and Metastatic Progression in Breast Cancer,” Nature Biomedical Engineering 7, no. 11 (2023): 1455-1472.

[41] A. Elosegui-Artola, A. Gupta, A. J. Najibi, et al., “Matrix Viscoelasticity Controls Spatiotemporal Tissue Organization,” Nature Materials 22, no. 1 (2023): 117-127.

[42] H. Deng, Y. Wang, Y. Yin, et al., “Effects of Matrix Viscoelasticity on Cell-Matrix Interaction, Actin Cytoskeleton Organization, and Apoptosis of Osteosarcoma MG-63 Cells,” Journal of Materials Chemistry B 12, no. 1 (2023): 222-232.

[43] J. Lou, R. Stowers, S. Nam, et al., “Stress Relaxing Hyaluronic Acid-Collagen Hydrogels Promote Cell Spreading, Fiber Remodeling, and Focal Adhesion Formation in 3D Cell Culture,” Biomaterials 154 (2018): 213-222.

[44] O. Chaudhuri, J. Cooper-White, P. A. Janmey, et al., “Effects of Extracellular Matrix Viscoelasticity on Cellular Behaviour,” Nature 584, no. 7822 (2020): 535-546.

[45] W. Fan, K. Adebowale, L. Vancza, et al., “Matrix Viscoelasticity Promotes Liver Cancer Progression in the Pre-Cirrhotic Liver,” Nature 626, no. 7999 (2024): 635-642.

[46] M. R. Blatchley, F. Hall, S. Wang, et al., “Hypoxia and Matrix Viscoelasticity Sequentially Regulate Endothelial Progenitor Cluster-Based Vasculogenesis,” Science Advances 5, no. 3 (2019): eaau7518.

[47] Y. Xu, G. Shi, J. Tang, et al., “ECM-Inspired Micro/Nanofibers for Modulating Cell Function and Tissue Generation,” Science Advances 6, no. 48 (2020): eabc2036.

[48] K. G. Soans, A. P. Ramos, J. Sidhaye, et al., “Collective Cell Migration During Optic Cup Formation Features Changing Cell-Matrix Interactions Linked to Matrix Topology,” Current Biology 32, no. 22 (2022): 4817-4831.e4819.

[49] C. Y. Su, A. Wu, Z. Dong, et al., “Tumor Stromal Topography Promotes Chemoresistance in Migrating Breast Cancer Cell Clusters,” Biomaterials 298 (2023): 122128.

[50] X. Sun, B. Wu, H. C. Chiang, et al., “Tumour DDR1 Promotes Collagen Fibre Alignment to Instigate Immune Exclusion,” Nature 599, no. 7886 (2021): 673-678.

[51] E. D. Tabdanov, N. J. Rodriguez-Merced, A. X. Cartagena-Rivera, et al., “Engineering T Cells to Enhance 3D Migration Through Structurally and Mechanically Complex Tumor Microenvironments,” Nature Communications 12, no. 1 (2021): 2815.

[52] Y. Peng, Z. Chen, Y. He, et al., “Non-Muscle Myosin II Isoforms Orchestrate Substrate Stiffness Sensing to Promote Cancer Cell Contractility and Migration,” Cancer Letters 524 (2022): 245-258.

[53] Y. Chen, P. Li, X. Chen, et al., “Endoplasmic Reticulum-Mitochondrial Calcium Transport Contributes to Soft Extracellular Matrix-Triggered Mitochondrial Dynamics and Mitophagy in Breast Carcinoma Cells,” Acta Biomaterialia 169 (2023): 192-208.

[54] O. Urzi, R. Gasparro, E. Costanzo, et al., “Three-Dimensional Cell Cultures: The Bridge Between in Vitro and in Vivo Models,” International Journal of Molecular Sciences 24, no. 15 (2023): 12046.

[55] Y. Song, Y. Zhang, Q. Qu, et al., “Biomaterials Based on Hyaluronic Acid, Collagen and Peptides for Three-Dimensional Cell Culture and Their Application in Stem Cell Differentiation,” International Journal of Biological Macromolecules 226 (2023): 14-36.

[56] J. Qu, F. S. Kalyani, L. Liu, et al., “Tumor Organoids: Synergistic Applications, Current Challenges, and Future Prospects in Cancer Therapy,” Cancer Communications (Lond) 41, no. 12 (2021): 1331-1353.

[57] W. Xiao, M. Pahlavanneshan, C. Y. Eun, et al., “Matrix Stiffness Mediates Pancreatic Cancer Chemoresistance Through Induction of Exosome Hypersecretion in a Cancer Associated Fibroblasts-Tumor Organoid Biomimetic Model,” Matrix Biology Plus 14 (2022): 100111.

[58] Z. Yang, H. Li, Y. Tian, et al., “Biofunctionalized Structure and Ingredient Mimicking Scaffolds Achieving Recruitment and Chondrogenesis for Staged Cartilage Regeneration,” Frontiers in Cell and Developmental Biology 9 (2021): 655440.

[59] K. C. Yang, Y. T. Yang, C. C. Wu, et al., “Bioinspired Collagen-Gelatin-Hyaluronic Acid-Chondroitin Sulfate Tetra-Copolymer Scaffold Biomimicking Native Cartilage Extracellular Matrix Facilitates Chondrogenesis of Human Synovium-Derived Stem Cells,” International Journal of Biological Macromolecules 240 (2023): 124400.

[60] T. Wu, Y. Chen, W. Liu, et al., “Ginsenoside Rb1/TGF-beta1 Loaded Biodegradable Silk Fibroin-Gelatin Porous Scaffolds for Inflammation Inhibition and Cartilage Regeneration,” Materials Science & Engineering. C, Materials for Biological Applications 111 (2020): 110757.

[61] A. K. Glaser, K. W. Bishop, L. A. Barner, et al., “A Hybrid Open-Top Light-Sheet Microscope for Versatile Multi-Scale Imaging of Cleared Tissues,” Nature Methods 19, no. 5 (2022): 613-619.

[62] G. A. Johnson, Y. Tian, D. G. Ashbrook, et al., “Merged Magnetic Resonance and Light Sheet Microscopy of the Whole Mouse Brain,” PNAS 120, no. 17 (2023): e2218617120.

[63] Q. Zhou, D. Nozdriukhin, Z. Chen, et al., “Depth-Resolved Localization Microangiography in the NIR-II Window,” Advanced Science (Weinh) 10, no. 1 (2022): e2204782.

[64] K. Zhang, Q. Feng, Z. Fang, et al., “Structurally Dynamic Hydrogels for Biomedical Applications: Pursuing a Fine Balance Between Macroscopic Stability and Microscopic Dynamics,” Chemical Reviews 121, no. 18 (2021): 11149-11193.

[65] Y. Shou, X. Y. Teo, K. Z. Wu, et al., “Dynamic Stimulations With Bioengineered Extracellular Matrix-Mimicking Hydrogels for Mechano Cell Reprogramming and Therapy,” Advanced Science (Weinh) 10, no. 21 (2023): e2300670.

[66] A. J. Ford and P. Rajagopalan, “Extracellular Matrix Remodeling in 3D: Implications in Tissue Homeostasis and Disease Progression,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 10, no. 4 (2018): e1503.

[67] H. S. Sonbol, “Extracellular Matrix Remodeling in Human Disease,” Journal of Microscopy and Ultrastructure 6, no. 3 (2018): 123-128.

[68] V. F. Fiore, S. S. Wong, C. Tran, et al., “αvβ3 Integrin Drives Fibroblast Contraction and Strain Stiffening of Soft Provisional Matrix During Progressive Fibrosis,” JCI Insight 3, no. 20 (2018): e97597.

[69] T. Shimizu & J. K. Liao, “Rho Kinases and Cardiac Remodeling,” Circulation Journal 80, no. 7 (2016): 1491-1498.

[70] S. Ferreira, N. Saraiva, P. Rijo, et al., “LOXL2 Inhibitors and Breast Cancer Progression,” Antioxidants (Basel) 10, no. 2 (2021): 312.

[71] W. Luo and T. Zhang, “Cancer-Associated Fibroblasts: A Key Target to Snatch Victory From Defeat in Therapy Resistance Associated With the Pancreatic Cancer Stroma,” Cancer Letters 567 (2023): 216279.

[72] J. W. Fawcett, M. Fyhn, P. Jendelova, et al., “The Extracellular Matrix and Perineuronal Nets in Memory,” Molecular Psychiatry 27, no. 8 (2022): 3192-3203.

[73] M. R. Blake, R. T. Gardner, H. Jin, et al., “Small Molecules Targeting PTPsigma-Trk Interactions Promote Sympathetic Nerve Regeneration,” Acs Chemical Neuroscience 13, no. 5 (2022): 688-699.

[74] R. Yang, Y. Zhang, J. Kang, et al., “Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury,” Aging and Disease 15, no. 1 (2024): 153-168.

[75] L. Knudsen and M. Ochs, “The Micromechanics of Lung Alveoli: Structure and Function of Surfactant and Tissue Components,” Histochemistry and Cell Biology 150, no. 6 (2018): 661-676.

[76] Y. Luo, N. Li, H. Chen, et al., “Spatial and Temporal Changes in Extracellular Elastin and Laminin Distribution During Lung Alveolar Development,” Scientific Reports 8, no. 1 (2018): 8334.

[77] J. Zhao, P. J. Sime, P. Bringas, J. Gauldie, & D. Warburton, “Adenovirus-mediated decorin gene transfer prevents TGF-β-induced inhibition of lung morphogenesis,” American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 2(1999): L412-L422.

[78] T. R. Cox and J. T. Erler, “Remodeling and Homeostasis of the Extracellular Matrix: Implications for Fibrotic Diseases and Cancer,” Disease Models & Mechanisms 4, no. 2 (2011): 165-178.

[79] J. J. Gokey, S. D. Patel, and J. A. Kropski, “The Role of Hippo/YAP Signaling in Alveolar Repair and Pulmonary Fibrosis,” Frontiers in Medicine (Lausanne) 8 (2021): 752316.

[80] A. Gimenez, P. Duch, M. Puig, et al., “Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-beta1 in Fibroblasts From Idiopathic Pulmonary Fibrosis Patients: Role of FAK/AKT,” International Journal of Molecular Sciences 18, no. 11 (2017): 2431.

[81] S. M. Lloyd & Y. He, “Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis,” Cells 13, no. 5 (2024): 438.

[82] T. Basak and S. Saraswati, “Editorial: Fibrotic Tissue Remodeling as a Driver of Disease Pathogenesis,” Frontiers in Molecular Biosciences 10 (2023): 1278388.

[83] A. C. Silva, C. Pereira, A. Fonseca, et al., “Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response,” Frontiers in Cell and Developmental Biology 8 (2020): 621644.

[84] Z. Yuan, Y. Li, S. Zhang, et al., “Extracellular Matrix Remodeling in Tumor Progression and Immune Escape: From Mechanisms to Treatments,” Molecular Cancer 22, no. 1 (2023): 48.

[85] K. E. de Visser and J. A. Joyce, “The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth,” Cancer Cell 41, no. 3 (2023): 374-403.

[86] A. Ray and P. P. Provenzano, “Aligned Forces: Origins and Mechanisms of Cancer Dissemination Guided by Extracellular Matrix Architecture,” Current Opinion in Cell Biology 72 (2021): 63-71.

[87] B. Han, X. Guan, M. Ma, et al., “Stiffened Tumor Microenvironment Enhances Perineural Invasion in Breast Cancer via Integrin Signaling,” Cellular Oncology (Dordr) 47, no. 3 (2024): 867-882.

[88] L. Gorchs and H. Kaipe, “Interactions Between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines,” Cancers (Basel) 13, no. 12 (2021): 2995.

[89] E. J. Kay, S. Zanivan, & A. Rufini, “Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion,” Current Opinion in Biotechnology 84 (2023): 103011.

[90] K. E. Rodrigues, M. H. B. Pontes, M. B. S. Cantao, et al., “The Role of Matrix Metalloproteinase-9 in Cardiac Remodeling and Dysfunction and as a Possible Blood Biomarker in Heart Failure,” Pharmacological Research 206 (2024): 107285.

[91] Y. Hao, D. Baker, and P. Ten Dijke, “TGF-beta-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis,” International Journal of Molecular Sciences 20, no. 11 (2019): 2767.

[92] A. O. Giarratana, C. M. Prendergast, M. M. Salvatore, & K. M. Capaccione, “TGF-β signaling: critical nexus of fibrogenesis and cancer,” Journal of Translational Medicine 22, no. 1 (2024).

[93] Y. Chen, Z. Li, F. Kong, et al., “Force-Regulated Spontaneous Conformational Changes of Integrins Alpha(5)Beta(1) and Alpha(V)Beta(3),” ACS Nano 18, no. 1 (2024): 299-313.

[94] M. H. Jo, J. Li, V. Jaumouille, et al., “Single-Molecule Characterization of Subtype-Specific beta1 Integrin Mechanics,” Nature Communications 13, no. 1 (2022): 7471.

[95] X. Di, X. Gao, L. Peng, et al., “Cellular Mechanotransduction in Health and Diseases: From Molecular Mechanism to Therapeutic Targets,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 282.

[96] J. J. F. Sleeboom, G. S. van Tienderen, K. Schenke-Layland, et al., “The Extracellular Matrix as Hallmark of Cancer and Metastasis: From Biomechanics to Therapeutic Targets,” Science Translational Medicine 16, no. 728 (2024): eadg3840.

[97] H. Hamidi, M. Pietila, and J. Ivaska, “The Complexity of Integrins in Cancer and New Scopes for Therapeutic Targeting,” British Journal of Cancer 115, no. 9 (2016): 1017-1023.

[98] J. Z. Kechagia, J. Ivaska, and P. Roca-Cusachs, “Integrins as Biomechanical Sensors of the Microenvironment,” Nature Reviews Molecular Cell Biology 20, no. 8 (2019): 457-473.

[99] P. B. Meagher, X. A. Lee, J. Lee, et al., “Cardiac Fibrosis: Key Role of Integrins in Cardiac Homeostasis and Remodeling,” Cells 10, no. 4 (2021): 770.

[100] S. D. Vallet, C. Berthollier, R. Salza, et al., “The Interactome of Cancer-Related Lysyl Oxidase and Lysyl Oxidase-Like Proteins,” Cancers (Basel) 13, no. 1 (2020): 71.

[101] H. Liu, Y. Zhou, H. Qiu, et al., “Rab26 Suppresses Migration and Invasion of Breast Cancer Cells Through Mediating Autophagic Degradation of Phosphorylated Src,” Cell Death & Disease 12, no. 4 (2021): 284.

[102] B. Cheng, W. Wan, G. Huang, et al., “Nanoscale Integrin Cluster Dynamics Controls Cellular Mechanosensing via FAKY397 Phosphorylation,” Science Advances 6, no. 10 (2020): eaax1909.

[103] S. B. Han, G. Lee, D. Kim, et al., “Selective Suppression of Integrin-Ligand Binding by Single Molecular Tension Probes Mediates Directional Cell Migration,” Advanced Science (Weinh) 11, no. 14 (2024): e2306497.

[104] C. Gaggioli, S. Hooper, C. Hidalgo-Carcedo, et al., “Fibroblast-Led Collective Invasion of Carcinoma Cells with Differing Roles for RhoGTPases in Leading and Following Cells,” Nature Cell Biology 9, no. 12 (2007): 1392-1400.

[105] M. S. Islam, A. Ciavattini, F. Petraglia, et al., “Extracellular Matrix in Uterine Leiomyoma Pathogenesis: A Potential Target for Future Therapeutics,” Human Reproduction Update 24, no. 1 (2018): 59-85.

[106] H. Chen, J. Yang, Q. Yang, et al., “Protein Prenylation in Mechanotransduction: Implications for Disease and Therapy,” Trends in Pharmacological Sciences 46, no. 2 (2025): 163-179.

[107] M. A. Riquelme, S. Gu, R. Hua, et al., “Mechanotransduction via the Coordinated Actions of Integrins, PI3K Signaling and Connexin Hemichannels,” Bone Research 9, no. 1 (2021): 8.

[108] E. Takai, R. Landesberg, R. W. Katz, et al., “Substrate Modulation of Osteoblast Adhesion Strength, Focal Adhesion Kinase Activation, and Responsiveness to Mechanical Stimuli,” Molecular & Cellular Biomechanics 3, no. 1 (2006): 1-12.

[109] P. Tapial Martinez, P. Lopez Navajas, and D. Lietha, “FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions,” Biomolecules 10, no. 2 (2020): 179.

[110] E. R. Hall, L. I. Bibby, and R. J. Slack, “Characterisation of a Novel, High Affinity and Selective alphavbeta6 Integrin RGD-Mimetic Radioligand,” Biochemical Pharmacology 117 (2016): 88-96.

[111] K. Ley, J. Rivera-Nieves, W. J. Sandborn, et al., “Integrin-Based Therapeutics: Biological Basis, Clinical Use and New Drugs,” Nat Rev Drug Discovery 15, no. 3 (2016): 173-183.

[112] E. Martinkova, A. Maglott, D. Y. Leger, et al., “alpha5beta1 Integrin Antagonists Reduce Chemotherapy-Induced Premature Senescence and Facilitate Apoptosis in Human Glioblastoma Cells,” International Journal of Cancer 127, no. 5 (2010): 1240-1248.

[113] B. Coste, J. Mathur, M. Schmidt, et al., “Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels,” Science 330, no. 6000 (2010): 55-60.

[114] J. Zheng, “Molecular Mechanism of TRP Channels,” Comprehensive Physiology 3, no. 1 (2013): 221-242.

[115] J. Geng, Y. Shi, J. Zhang, et al., “TLR4 Signalling via Piezo1 Engages and Enhances the Macrophage Mediated Host Response During Bacterial Infection,” Nature Communications 12, no. 1 (2021): 3519.

[116] W. Sun, S. Chi, Y. Li, et al., “The Mechanosensitive Piezo1 Channel Is Required for Bone Formation,” Elife 8 (2019): e47454.

[117] S. Wang, R. Chennupati, H. Kaur, et al., “Endothelial Cation Channel Piezo1 Controls Blood Pressure by Mediating Flow-Induced ATP Release,” Journal of Clinical Investigation 126, no. 12 (2016): 4527-4536.

[118] Y. Jiang, X. Yang, J. Jiang, et al., “Structural Designs and Mechanogating Mechanisms of the Mechanosensitive Piezo Channels,” Trends in Biochemical Sciences 46, no. 6 (2021): 472-488.

[119] M. Yao, A. Tijore, D. Cheng, et al., “Force- and Cell State-Dependent Recruitment of Piezo1 Drives Focal Adhesion Dynamics and Calcium Entry,” Science Advances 8, no. 45 (2022): eabo1461.

[120] O. F. Harraz, N. R. Klug, A. J. Senatore, et al., “Piezo1 is a Mechanosensor Channel in Central Nervous System Capillaries,” Circulation Research 130, no. 10 (2022): 1531-1546.

[121] J. He, X. Cheng, B. Fang, et al., “Mechanical Stiffness Promotes Skin Fibrosis via Piezo1-Wnt2/Wnt11-CCL24 Positive Feedback Loop,” Cell Death & Disease 15, no. 1 (2024): 84.

[122] N. Bavi, J. Richardson, C. Heu, et al., “PIEZO1-Mediated Currents Are Modulated by Substrate Mechanics,” ACS Nano 13, no. 11 (2019): 13545-13559.

[123] W. Gao, H. Hasan, D. E. Anderson, et al., “The Role of Mechanically-Activated Ion Channels Piezo1, Piezo2, and TRPV4 in Chondrocyte Mechanotransduction and Mechano-Therapeutics for Osteoarthritis,” Frontiers in Cell and Developmental Biology 10 (2022): 885224.

[124] W. H. Lee, L. Y. Choong, T. H. Jin, et al., “TRPV4 Plays a Role in Breast Cancer Cell Migration via Ca(2+)-Dependent Activation of AKT and Downregulation of E-Cadherin Cell Cortex Protein,” Oncogenesis 6, no. 5 (2017): e338.

[125] S. Sharma, R. Goswami, D. X. Zhang, et al., “TRPV4 Regulates Matrix Stiffness and TGFbeta1-Induced Epithelial-Mesenchymal Transition,” Journal of Cellular and Molecular Medicine 23, no. 2 (2019): 761-774.

[126] S. M. Swain, J. M. Romac, S. R. Vigna, et al., “Piezo1-Mediated Stellate Cell Activation Causes Pressure-Induced Pancreatic Fibrosis in Mice,” JCI Insight 7, no. 8 (2022): e158288.

[127] X. Chen, W. Lu, C. Lu, et al., “The CaSR/TRPV4 Coupling Mediates Pro-Inflammatory Macrophage Function,” Acta Physiologica (Oxf) 237, no. 4 (2023): e13926.

[128] H. Sun, Z. Sun, X. Xu, et al., “Blocking TRPV4 Ameliorates Osteoarthritis by Inhibiting M1 Macrophage Polarization via the ROS/NLRP3 Signaling Pathway,” Antioxidants (Basel) 11, no. 12 (2022): 2315.

[129] H. Y. K. Kaan, A. Y. L. Sim, S. K. J. Tan, et al., “Targeting YAP/TAZ-TEAD Protein-Protein Interactions Using Fragment-Based and Computational Modeling Approaches,” PLoS ONE 12, no. 6 (2017): e0178381.

[130] B. J. Thompson, “YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy,” BioEssays 42, no. 5 (2020): e1900162.

[131] L. Niu, Y. Jia, M. Wu, et al., “Matrix Stiffness Controls Cardiac Fibroblast Activation Through Regulating YAP via AT(1) R,” Journal of Cellular Physiology 235, no. 11 (2020): 8345-8357.

[132] A. N. Gargalionis, K. A. Papavassiliou, and A. G. Papavassiliou, “Targeting the YAP/TAZ Mechanotransducers in Solid Tumour Therapeutics,” Journal of Cellular and Molecular Medicine 27, no. 13 (2023): 1911-1914.

[133] Y. Guo, Z. Zhu, Z. Huang, et al., “CK2-Induced Cooperation of HHEX With the YAP-TEAD4 Complex Promotes Colorectal Tumorigenesis,” Nature Communications 13, no. 1 (2022): 4995.

[134] Luo, J., H. Zou, Y. Guo, et al., “The oncogenic roles and clinical implications of YAP/TAZ in breast cancer,” British Journal of Cancer. (2023).

[135] Z. Liu, L. Wang, H. Xu, et al., “Heterogeneous Responses to Mechanical Force of Prostate Cancer Cells Inducing Different Metastasis Patterns,” Advanced Science (Weinh) 7, no. 15 (2020): 1903583.

[136] J. H. Koo and K. L. Guan, “Interplay Between YAP/TAZ and Metabolism,” Cell Metabolism 28, no. 2 (2018): 196-206.

[137] Y. Wei, V. L. Z. Hui, Y. Chen, R. Han, X. Han, & Y. Guo, “YAP/TAZ: Molecular pathway and disease therapy,” MedComm 4, no. 4 (2023).

[138] K. E. Scott, S. I. Fraley, and P. Rangamani, “A Spatial Model of YAP/TAZ Signaling Reveals How Stiffness, Dimensionality, and Shape Contribute to Emergent Outcomes,” PNAS 118, no. 20 (2021): e2021571118.

[139] A. W. Holle, J. L. Young, K. J. Van Vliet, et al., “Cell-Extracellular Matrix Mechanobiology: Forceful Tools and Emerging Needs for Basic and Translational Research,” Nano Letters 18, no. 1 (2018): 1-8.

[140] S. He, P. Lei, W. Kang, et al., “Stiffness Restricts the Stemness of the Intestinal Stem Cells and Skews Their Differentiation Toward Goblet Cells,” Gastroenterology 164, no. 7 (2023): 1137-1151.e1115.

[141] Y. Peng, Z. Chen, Y. Chen, et al., “ROCK Isoforms Differentially Modulate Cancer Cell Motility by Mechanosensing the Substrate Stiffness,” Acta Biomaterialia 88 (2019): 86-101.

[142] Y. Chen, P. Li, Y. Peng, et al., “Protective Autophagy Attenuates Soft Substrate-Induced Apoptosis Through ROS/JNK Signaling Pathway in Breast Cancer Cells,” Free Radical Biology and Medicine 172 (2021): 590-603.

[143] H. Bougherara, A. Mansuet-Lupo, M. Alifano, et al., “Real-Time Imaging of Resident T Cells in Human Lung and Ovarian Carcinomas Reveals How Different Tumor Microenvironments Control T Lymphocyte Migration,” Frontiers in Immunology 6 (2015): 500.

[144] C. W. Huo, G. Chew, P. Hill, et al., “High Mammographic Density Is Associated With an Increase in Stromal Collagen and Immune Cells Within the Mammary Epithelium,” Breast Cancer Research 17, no. 1 (2015): 79.

[145] D. E. Kuczek, A. M. H. Larsen, M. L. Thorseth, et al., “Collagen Density Regulates the Activity of Tumor-Infiltrating T Cells,” Journal for ImmunoTherapy of Cancer 7, no. 1 (2019): 68.

[146] M. Chakraborty, K. Chu, A. Shrestha, et al., “Mechanical Stiffness Controls Dendritic Cell Metabolism and Function,” Cell Reports 34, no. 2 (2021): 108609.

[147] J. Zhang, J. Li, Y. Hou, et al., “Osr2 Functions as a Biomechanical Checkpoint to Aggravate CD8(+) T Cell Exhaustion in Tumor,” Cell 187, no. 13 (2024): 3409-3426.e3424.

[148] Y. C. Chuang, H. M. Chang, C. Y. Li, et al., “Reactive Oxygen Species and Inflammatory Responses of Macrophages to Substrates with Physiological Stiffness,” ACS Applied Materials & Interfaces 12, no. 43 (2020): 48432-48441.

[149] C. S. Bonder, S. R. Clark, M. U. Norman, et al., “Use of CD44 by CD4+ Th1 and Th2 Lymphocytes to Roll and Adhere,” Blood 107, no. 12 (2006): 4798-4806.

[150] D. Ly, Q. Li, R. Navab, et al., “Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma,” Cancers (Basel) 14, no. 1 (2021): 205.

[151] A. Altieri, G. V. Visser, and M. B. Buechler, “Enter the Matrix: Fibroblast-Immune Cell Interactions Shape Extracellular Matrix Deposition in Health and Disease,” F1000Research 13 (2024): 119.

[152] L. C. Bockelmann, T. Felix, S. Calabro, et al., “YKL-40 Protein Expression in Human Tumor Samples and Human Tumor Cell Line Xenografts: Implications for Its Use in Tumor Models,” Cellular Oncology (Dordr) 44, no. 5 (2021): 1183-1195.

[153] E. Helal-Neto, R. M. Brandao-Costa, R. Saldanha-Gama, et al., “Priming Endothelial Cells With a Melanoma-Derived Extracellular Matrix Triggers the Activation of alphavbeta3/VEGFR2 Axis,” Journal of Cellular Physiology 231, no. 11 (2016): 2464-2473.

[154] R. Shao, K. Hamel, L. Petersen, et al., “YKL-40, a Secreted Glycoprotein, Promotes Tumor Angiogenesis,” Oncogene 28, no. 50 (2009): 4456-4468.

[155] C. Bonnans, J. Chou, and Z. Werb, “Remodelling the Extracellular Matrix in Development and Disease,” Nature Reviews Molecular Cell Biology 15, no. 12 (2014): 786-801.

[156] S. S. Acharya and C. N. Kundu, “Havoc in Harmony: Unravelling the Intricacies of Angiogenesis Orchestrated by the Tumor Microenvironment,” Cancer Treatment Reviews 127 (2024): 102749.

[157] O. A. Forrest, B. Dobosh, S. A. Ingersoll, et al., “Neutrophil-Derived Extracellular Vesicles Promote Feed-Forward Inflammasome Signaling in Cystic Fibrosis Airways,” Journal of Leukocyte Biology 112, no. 4 (2022): 707-716.

[158] L. He, Q. Kang, K. I. Chan, et al., “The Immunomodulatory Role of Matrix Metalloproteinases in Colitis-Associated Cancer,” Frontiers in Immunology 13 (2022): 1093990.

[159] T. J. Rabelink, B. M. van den Berg, M. Garsen, et al., “Heparanase: Roles in Cell Survival, Extracellular Matrix Remodelling and the Development of Kidney Disease,” Nature Reviews Nephrology 13, no. 4 (2017): 201-212.

[160] T. Shi, L. Denney, H. An, et al., “Alveolar and Lung Interstitial Macrophages: Definitions, Functions, and Roles in Lung Fibrosis,” Journal of Leukocyte Biology 110, no. 1 (2021): 107-114.

[161] F. C. Simoes, T. J. Cahill, A. Kenyon, et al., “Macrophages Directly Contribute Collagen to Scar Formation During Zebrafish Heart Regeneration and Mouse Heart Repair,” Nature Communications 11, no. 1 (2020): 600.

[162] H. E. Talbott, S. Mascharak, M. Griffin, et al., “Wound Healing, Fibroblast Heterogeneity, and Fibrosis,” Cell Stem Cell 29, no. 8 (2022): 1161-1180.

[163] L. Yan, J. Wang, X. Cai, et al., “Macrophage Plasticity: Signaling Pathways, Tissue Repair, and Regeneration,” MedComm 5, no. 8 (2024): e658.

[164] J. Huang, L. Zhang, D. Wan, et al., “Extracellular Matrix and Its Therapeutic Potential for Cancer Treatment,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 153.

[165] S. Kauppila, F. Stenback, J. Risteli, et al., “Aberrant Type I and Type III Collagen Gene Expression in Human Breast Cancer in Vivo,” Journal of Pathology 186, no. 3 (1998): 262-268.

[166] M. Kamei, W. B. Saunders, K. J. Bayless, et al., “Endothelial Tubes Assemble From Intracellular Vacuoles in Vivo,” Nature 442, no. 7101 (2006): 453-456.

[167] A. Hielscher, K. Ellis, C. Qiu, et al., “Fibronectin Deposition Participates in Extracellular Matrix Assembly and Vascular Morphogenesis,” PLoS ONE 11, no. 1 (2016): e0147600.

[168] S. Mizuno, M. A. Bustos, Y. Hayashi, et al., “Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes,” Clinical and Translational Medicine 14, no. 11 (2024): Portico.

[169] D. Wang, Y. Li, H. Ge, et al., “The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC,” Cancers (Basel) 14, no. 16 (2022): 3998.

[170] C. Tian, Y. Huang, K. R. Clauser, et al., “Suppression of Pancreatic Ductal Adenocarcinoma Growth and Metastasis by Fibrillar Collagens Produced Selectively by Tumor Cells,” Nature Communications 12, no. 1 (2021): 2328.

[171] H. Jiang, X. Liu, B. L. Knolhoff, et al., “Development of Resistance to FAK Inhibition in Pancreatic Cancer Is Linked to Stromal Depletion,” Gut 69, no. 1 (2020): 122-132.

[172] H. Wang, R. Ren, Z. Yang, et al., “The COL11A1/Akt/CREB Signaling Axis Enables Mitochondrial-Mediated Apoptotic Evasion to Promote Chemoresistance in Pancreatic Cancer Cells Through Modulating BAX/BCL-2 Function,” Journal of Cancer 12, no. 5 (2021): 1406-1420.

[173] W. Du, X. Xia, F. Hu, et al., “Extracellular Matrix Remodeling in the Tumor Immunity,” Frontiers in Immunology 14 (2023): 1340634.

[174] V. Sarohi, S. Chakraborty, and T. Basak, “Exploring the Cardiac ECM During Fibrosis: A New Era With Next-Gen Proteomics,” Frontiers in Molecular Biosciences 9 (2022): 1030226.

[175] K. Sun, X. Li, and P. E. Scherer, “Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives,” Comprehensive Physiology 13, no. 1 (2023): 4387-4407.

[176] G. Sygitowicz, A. Maciejak-Jastrzebska, and D. Sitkiewicz, “A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation,” Journal of Clinical Medicine 10, no. 19 (2021): 4430.

[177] S. M. Lloyd and Y. He, “Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis,” Cells 13, no. 5 (2024): 438.

[178] A. Larson, C. J. Codden, G. S. Huggins, et al., “Altered Intercellular Communication and Extracellular Matrix Signaling as a Potential Disease Mechanism in Human Hypertrophic Cardiomyopathy,” Scientific Reports 12, no. 1 (2022): 5211.

[179] J. Hsieh, K. L. Becklin, S. Givens, et al., “Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy,” Frontiers in Cell and Developmental Biology 10 (2022): 894635.

[180] A. Di Nubila, G. Dilella, R. Simone, et al., “Vascular Extracellular Matrix in Atherosclerosis,” International Journal of Molecular Sciences 25, no. 22 (2024): 12017.

[181] C. Gialeli, A. Shami, and I. Goncalves, “Extracellular Matrix: Paving the Way to the Newest Trends in Atherosclerosis,” Current Opinion in Lipidology 32, no. 5 (2021): 277-285.

[182] D. Singh, V. Rai, and D. K. Agrawal, “Non-Coding RNAs in Regulating Plaque Progression and Remodeling of Extracellular Matrix in Atherosclerosis,” International Journal of Molecular Sciences 23, no. 22 (2022): 13731.

[183] Y. Su, J. Yuan, F. Zhang, et al., “MicroRNA-181a-5p and microRNA-181a-3p Cooperatively Restrict Vascular Inflammation and Atherosclerosis,” Cell Death & Disease 10, no. 5 (2019): 365.

[184] Q. Yang, C. Yan, Y. Sun, et al., “Extracellular Matrix Remodeling Alleviates Memory Deficits in Alzheimer's Disease by Enhancing the Astrocytic Autophagy-Lysosome Pathway,” Advanced Science (Weinh) 11, no. 31 (2024): e2400480.

[185] L. Hohn, W. Hussler, A. Richter, et al., “Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer's Disease Patients,” International Journal of Molecular Sciences 24, no. 6 (2023): 5532.

[186] A. Freitas, M. Aroso, A. Barros, et al., “Characterization of the Striatal Extracellular Matrix in a Mouse Model of Parkinson's Disease,” Antioxidants (Basel) 10, no. 7 (2021): 1095.

[187] F. N. Soria, C. Paviolo, E. Doudnikoff, et al., “Synucleinopathy Alters Nanoscale Organization and Diffusion in the Brain Extracellular Space Through Hyaluronan Remodeling,” Nature Communications 11, no. 1 (2020): 3440.

[188] S. Ghorbani and V. W. Yong, “The Extracellular Matrix as Modifier of Neuroinflammation and Remyelination in Multiple Sclerosis,” Brain 144, no. 7 (2021): 1958-1973.

[189] A. G. Thompson, E. Gray, S. M. Heman-Ackah, et al., “Extracellular Vesicles in Neurodegenerative Disease—Pathogenesis to Biomarkers,” Nature Reviews Neurology 12, no. 6 (2016): 346-357.

[190] Y. Xiao, S. K. Wang, Y. Zhang, et al., “Role of Extracellular Vesicles in Neurodegenerative Diseases,” Progress in Neurobiology 201 (2021): 102022.

[191] M. R. Wilson, S. Satapathy, and M. Vendruscolo, “Extracellular Protein Homeostasis in Neurodegenerative Diseases,” Nature Reviews Neurology 19, no. 4 (2023): 235-245.

[192] V. Ahmad, “Prospective of Extracellular Matrix and Drug Correlations in Disease Management,” Asian Journal of Pharmaceutical Sciences 16, no. 2 (2021): 147-160.

[193] E. Van Cutsem, M. A. Tempero, D. Sigal, et al., “Randomized Phase III Trial of Pegvorhyaluronidase alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma,” Journal of Clinical Oncology 38, no. 27 (2020): 3185-3194.

[194] J. Vansteenkiste, F. Barlesi, C. F. Waller, et al., “Cilengitide Combined With Cetuximab and Platinum-Based Chemotherapy as First-Line Treatment in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients: Results of an Open-Label, Randomized, Controlled Phase II Study (CERTO),” Annals of Oncology 26, no. 8 (2015): 1734-1740.

[195] J. L. Chitty, M. Yam, L. Perryman, et al., “A First-in-Class Pan-Lysyl Oxidase Inhibitor Impairs Stromal Remodeling and Enhances Gemcitabine Response and Survival in Pancreatic Cancer,” Nature Cancer 4, no. 9 (2023): 1326-1344.

[196] D. Thorburn, D. J. Leeming, W. T. Barchuk, et al., “Serologic Extracellular Matrix Remodeling Markers Are Related to Fibrosis Stage and Prognosis in a Phase 2b Trial of Simtuzumab in Patients With Primary Sclerosing Cholangitis,” Hepatology Communications 8, no. 7 (2024): e0467.

[197] A. J. Muir, C. Levy, H. L. A. Janssen, et al., “Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease,” Hepatology 69, no. 2 (2019): 684-698.

[198] J. C. Soria, H. K. Gan, S. P. Blagden, et al., “A Phase I, Pharmacokinetic and Pharmacodynamic Study of GSK2256098, a Focal Adhesion Kinase Inhibitor, in Patients With Advanced Solid Tumors,” Annals of Oncology 27, no. 12 (2016): 2268-2274.

[199] G. Patti, A. Nusca, F. Mangiacapra, et al., “Point-of-Care Measurement of Clopidogrel Responsiveness Predicts Clinical Outcome in Patients Undergoing Percutaneous Coronary Intervention Results of the ARMYDA-PRO (Antiplatelet Therapy for Reduction of MYocardial Damage During Angioplasty-Platelet Reactivity Predicts Outcome) Study,” Journal of the American College of Cardiology 52, no. 14 (2008): 1128-1133.

[200] Y. Ren, W. Liu, L. Zhang, et al., “Milk Fat Globule EGF Factor 8 Restores Mitochondrial Function via Integrin-Medicated Activation of the FAK-STAT3 Signaling Pathway in Acute Pancreatitis,” Clinical and Translational Medicine 11, no. 2 (2021): e295.

[201] Infante, J. R., D. R. Camidge, L. R. Mileshkin, et al., “Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors,” Journal of Clinical Oncology 30, no. 13 (2012): 1527-1533.

[202] D. Jiang, J. Zhao, J. Zheng, et al., “LOX-Mediated ECM Mechanical Stress Induces Piezo1 Activation in Hypoxic-Ischemic Brain Damage and Identification of Novel Inhibitor of LOX,” Redox Biology 76 (2024): 103346.

[203] W. Tang, Y. Hu, K. Tu, et al., “Targeting Trop2 by Bruceine D Suppresses Breast Cancer Metastasis by Blocking Trop2/Beta-Catenin Positive Feedback Loop,” Journal of Advanced Research 58 (2024): 193-210.

[204] K. S. Thorneloe, M. Cheung, D. A. Holt, et al., “Properties of the TRPV4 Agonist GSK1016790A and the TRPV4 Antagonist GSK2193874,” Physiological Reviews 97, no. 4 (2017): 1231-1232.

[205] E. L. Evans, K. Cuthbertson, N. Endesh, et al., “Yoda1 Analogue (Dooku1) Which Antagonizes Yoda1-Evoked Activation of Piezo1 and Aortic Relaxation,” British Journal of Pharmacology 175, no. 10 (2018): 1744-1759.

[206] PEGPH20 May Improve Standard-of-Care Therapy in Pancreatic Cancer. Cancer Discovery 8, no. 2 (2018): 136-136.

[207] R. Stupp, M. E. Hegi, T. Gorlia, et al., “Cilengitide Combined With Standard Treatment for Patients With Newly Diagnosed Glioblastoma With Methylated MGMT Promoter (CENTRIC EORTC 26071-22072 Study): A Multicentre, Randomised, Open-Label, Phase 3 Trial,” The Lancet Oncology 15, no. 10 (2014): 1100-1108.

[208] P. Hersey, J. Sosman, S. O'Day, et al., “A Randomized Phase 2 Study of Etaracizumab, a Monoclonal Antibody Against Integrin Alpha(v)Beta(3), + or—Dacarbazine in Patients with Stage IV Metastatic Melanoma,” Cancer 116, no. 6 (2010): 1526-1534.

[209] Infante, J. R., D. R. Camidge, L. R. Mileshkin, et al., “Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors,” Journal of Clinical Oncology 30, no. 13 (2012): 1527-1533.

[210] D. A. Fennell, P. Baas, P. Taylor, et al., “Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients with Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study,” Journal of Clinical Oncology 37, no. 10 (2019): 790-798.

[211] A. U. Wells, “Pamrevlumab in Idiopathic Pulmonary Fibrosis,” The Lancet Respiratory Medicine 8, no. 1 (2020): 2-3.

[212] V. J. Picozzi, “Pancreatic Cancer: New Approaches to Drug Therapy,” International Journal of Surgery 110, no. 10 (2024): 6070-6080.

[213] Richeldi, L., E. R. Fernández Pérez, U. Costabel, et al., “Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial,” The Lancet Respiratory Medicine 8, no. 1 (2020): 25-33.

[214] A. N. Hosein, R. A. Brekken, and A. Maitra, “Pancreatic Cancer Stroma: An Update on Therapeutic Targeting Strategies,” Nature Reviews Gastroenterology & Hepatology 17, no. 8 (2020): 487-505.

[215] S. K. Pal and C. Tangen, “A Comparison of Sunitinib With Cabozantinib, Crizotinib, and Savolitinib for Treatment of Advanced Papillary Renal Cell Carcinoma: A Randomised, Open-Label, Phase 2 Trial,” Lancet 397, no. 10275 (2021): 695-703.

[216] A. Lopez, K. Harada, M. Vasilakopoulou, et al., “Targeting Angiogenesis in Colorectal Carcinoma,” Drugs 79, no. 1 (2019): 63-74.

[217] H. Kim, J. Seo, Y. Lee, et al., “The Current State of the Osteoarthritis Drug Development Pipeline: A Comprehensive Narrative Review of the Present Challenges and Future Opportunities,” Therapeutic Advances in Musculoskeletal Disease 14 (2022): 1759720×221085952.

[218] N. Gerwin, C. Scotti, C. Halleux, et al., “Angiopoietin-Like 3-Derivative LNA043 for Cartilage Regeneration in Osteoarthritis: A Randomized Phase 1 Trial,” Nature Medicine 28, no. 12 (2022): 2633-2645.

[219] W. Pao and N. Girard, “New Driver Mutations in Non-Small-Cell Lung Cancer,” The Lancet Oncology 12, no. 2 (2011): 175-180.

[220] A. H. Burstein, M. Sabbagh, R. Andrews, et al., “Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 5, no. 2 (2018): 149-154.

[221] M. Magna, G. H. Hwang, A. McIntosh, et al., “RAGE Inhibitor TTP488 (Azeliragon) Suppresses Metastasis in Triple-Negative Breast Cancer,” NPJ Breast Cancer 9, no. 1 (2023): 59.

[222] J. Wei, J. Yao, M. Yan, et al., “The Role of Matrix Stiffness in Cancer Stromal Cell Fate and Targeting Therapeutic Strategies,” Acta Biomaterialia 150 (2022): 34-47.

[223] D. V. Bhalani, B. Nutan, A. Kumar, et al., “Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics,” Biomedicines 10, no. 9 (2022): 2055.

[224] M. I. Khan, M. I. Hossain, M. K. Hossain, et al., “Recent Progress in Nanostructured Smart Drug Delivery Systems for Cancer Therapy: A Review,” ACS Applied Bio Materials 5, no. 3 (2022): 971-1012.

[225] M. Benedikt Brenner, M. Wust, M. Kuentz, et al., “High Loading of Lipophilic Compounds in Mesoporous Silica for Improved Solubility and Dissolution Performance,” International Journal of Pharmaceutics 654 (2024): 123946.

[226] A. Figueiras, C. Domingues, I. Jarak, et al., “New Advances in Biomedical Application of Polymeric Micelles,” Pharmaceutics 14, no. 8 (2022): 1700.

[227] Y. Liu, Y. Liang, J. Yuhong, et al., “Advances in Nanotechnology for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs,” Drug Design, Development and Therapy 18 (2024): 1469-1495.

[228] H. Cho, S. I. Jeon, C. H. Ahn, et al., “Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation,” Pharmaceutics 14, no. 4 (2022): 728.

[229] S. Teixeira, M. A. Carvalho, and E. M. S. Castanheira, “Functionalized Liposome and Albumin-Based Systems as Carriers for Poorly Water-Soluble Anticancer Drugs: An Updated Review,” Biomedicines 10, no. 2 (2022): 486.

[230] H. Zhou, J. He, R. Liu, et al., “Microenvironment-Responsive Metal-Phenolic Network Release Platform With ROS Scavenging, Anti-Pyroptosis, and ECM Regeneration for Intervertebral Disc Degeneration,” Bioactive Materials 37 (2024): 51-71.

[231] S. Duan, F. Sun, P. Qiao, et al., “Detachable Dual-Targeting Nanoparticles for Improving the Antitumor Effect by Extracellular Matrix Depletion,” ACS Biomaterials Science & Engineering 9, no. 3 (2023): 1437-1449.

[232] Z. Chen, L. Long, J. Wang, et al., “Enhanced Tumor Site Accumulation and Therapeutic Efficacy of Extracellular Matrix-Drug Conjugates Targeting Tumor Cells,” Small 20, no. 40 (2024): e2402040.

[233] L. F. Zhang, X. H. Wang, C. L. Zhang, et al., “Sequential Nano-Penetrators of Capillarized Liver Sinusoids and Extracellular Matrix Barriers for Liver Fibrosis Therapy,” ACS Nano 16, no. 9 (2022): 14029-14042.

[234] M. Chen, B. Chen, X. Ge, et al., “Targeted Nanodrugs to Destroy the Tumor Extracellular Matrix Barrier for Improving Drug Delivery and Cancer Therapeutic Efficacy,” Molecular Pharmaceutics 20, no. 5 (2023): 2389-2401.

[235] T. Geuens, F. A. A. Ruiter, A. Schumacher, et al., “Thiol-Ene Cross-Linked Alginate Hydrogel Encapsulation Modulates the Extracellular Matrix of Kidney Organoids by Reducing Abnormal Type 1a1 Collagen Deposition,” Biomaterials 275 (2021): 120976.

[236] L. Qi, B. W. Duan, H. Wang, et al., “Reactive Oxygen Species-Responsive Nanoparticles Toward Extracellular Matrix Normalization for Pancreatic Fibrosis Regression,” Advanced Science (Weinh) 11, no. 19 (2024): e2401254.

[237] Q. Liu, J. Wang, H. Sun, et al., “Targeting RORgamma Inhibits the Growth and Metastasis of Hepatocellular Carcinoma,” Molecular Therapy 32, no. 3 (2024): 749-765.

[238] H. Wang, H. Sun, J. Huang, et al., “Therapeutic Targeting ERRgamma Suppresses Metastasis via Extracellular Matrix Remodeling in Small Cell Lung Cancer,” EMBO Molecular Medicine 16, no. 9 (2024): 2043-2059.

[239] M. Zhan, X. Yu, W. Zhao, et al., “Extracellular Matrix-Degrading STING Nanoagonists for Mild NIR-II Photothermal-Augmented Chemodynamic-Immunotherapy,” Journal of Nanobiotechnology 20, no. 1 (2022): 23.

[240] N. Jia, Q. Wang, W. Li, et al., “Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment,” Advanced Healthcare Materials 13, no. 20 (2024): e2400219.

[241] L. Zong, H. Xu, H. Zhang, et al., “A Review of Matrix Metalloproteinase-2-Sensitive Nanoparticles as a Novel Drug Delivery for Tumor Therapy,” International Journal of Biological Macromolecules 262, no. Pt 2 (2024): 130043.

[242] J. Gao, H. Qin, F. Wang, et al., “Hyperthermia-Triggered Biomimetic Bubble Nanomachines,” Nature Communications 14, no. 1 (2023): 4867.

[243] C. Berard, S. Desgranges, N. Dumas, et al., “Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption,” Pharmaceutics 14, no. 7 (2022): 1498.

[244] Y. Hu, J. Wei, Y. Shen, et al., “Barrier-Breaking Effects of Ultrasonic Cavitation for Drug Delivery and Biomarker Release,” Ultrasonics Sonochemistry 94 (2023): 106346.

[245] C. Li, Y. Qiu, and Y. Zhang, “Research Progress on Therapeutic Targeting of Cancer-Associated Fibroblasts to Tackle Treatment-Resistant NSCLC,” Pharmaceuticals (Basel) 15, no. 11 (2022): 1411.

[246] D. Hu, Z. Li, B. Zheng, et al., “Cancer-Associated Fibroblasts in Breast Cancer: Challenges and Opportunities,” Cancer Communications (Lond) 42, no. 5 (2022): 401-434.

[247] C. Zhou, X. He, C. Tong, et al., “Cancer-Associated Adipocytes Promote the Invasion and Metastasis in Breast Cancer Through LIF/CXCLs Positive Feedback Loop,” International Journal of Biological Sciences 18, no. 4 (2022): 1363-1380.

[248] B. M. Prive, M. A. Boussihmad, B. Timmermans, et al., “Fibroblast Activation Protein-Targeted Radionuclide Therapy: Background, Opportunities, and Challenges of First (pre)Clinical Studies,” European Journal of Nuclear Medicine and Molecular Imaging 50, no. 7 (2023): 1906-1918.

[249] M. M. Koczorowska, S. Tholen, F. Bucher, et al., “Fibroblast Activation Protein-alpha, a Stromal Cell Surface Protease, Shapes Key Features of Cancer Associated Fibroblasts Through Proteome and Degradome Alterations,” Molecular Oncology 10, no. 1 (2016): 40-58.

[250] R. A. Glabman, P. L. Choyke, and N. Sato, “Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy,” Cancers (Basel) 14, no. 16 (2022): 3906.

[251] A. A. Fitzgerald and L. M. Weiner, “The Role of Fibroblast Activation Protein in Health and Malignancy,” Cancer and Metastasis Reviews 39, no. 3 (2020): 783-803.

[252] Z. Fang, Q. Meng, J. Xu, et al., “Signaling Pathways in Cancer-Associated Fibroblasts: Recent Advances and Future Perspectives,” Cancer Communications (Lond) 43, no. 1 (2023): 3-41.

[253] R. Srikuea and M. Hirunsai, “TGF-beta1 Stimulation and VDR-Dependent Activation Modulate Calcitriol Action on Skeletal Muscle Fibroblasts and Smad Signalling-Associated Fibrogenesis,” Scientific Reports 13, no. 1 (2023): 13811.

[254] Tyan, S.-W., W.-H. Kuo, C.-K. Huang, et al., “Breast Cancer Cells Induce Cancer-Associated Fibroblasts to Secrete Hepatocyte Growth Factor to Enhance Breast Tumorigenesis,” PLoS ONE 6, no. 1 (2011): e15313.

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