Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.006
Floriane S. Tissot , Soline Estrach , Laetitia Seguin , Laurence Cailleteau , Ayelet Levy , Daniel Aberdam , Chloé C. Féral
Extracellular vesicles (EVs) mediate intercellular communication. EVs are composed of a lipid bilayer and contain cytosolic proteins and RNAs. Studies highlight EVs striking functions in cell-cell crosstalk. Here, we found that small EVs can transfer functional signaling molecules through their lipid bilayer and participate in skin homeostasis. We identified a transmembrane protein CD98hc (a.k.a. SLC3A2), an integrin co-receptor (Itgb1 and Itgb3), implicated in epidermis homeostasis via its capacity in regulating extracellular matrix, as an important mediator of EV-based intercellular communication in vivo. We first demonstrated that healthy dermal fibroblasts produced and secreted EVs bearing characteristic of exosome-like small EVs (sEVs). We show that CD98hc, Itgb1 co-receptor, is present at the surface of sEVs, transferred and stabilized at the plasma membrane. The transferred complex is functional on recipient cells both in vitro and in vivo. Indeed, treatment with sEVs from WT, but not KO cells rescued migratory defects observed either in CD98hc KO dermal fibroblasts or in keratinocytes in vitro. Furthermore, injection of sEVs at the margins of wound in impaired wound healing mouse models (epidermal CD98hc KO mice exhibiting healing defect and elderly mice) improved wound closure in vivo. CD98hc complex transferred from sEVs remained stabilized at least 7 days after injection. Thus, our findings reveal that in vivo treatment with sEVs containing integrin co-receptor CD98hc could improve multiple skin afflictions.
细胞外囊泡（EV）是细胞间通信的媒介。细胞外小泡由脂质双分子层组成，含有细胞膜蛋白质和 RNA。研究强调了EVs在细胞-细胞串联中的显著功能。在这里，我们发现小的EV可通过其脂质双分子层传递功能性信号分子，并参与皮肤稳态。我们发现了一种跨膜蛋白 CD98hc（又名 SLC3A2），它是一种整合素共受体（Itgb1 和 Itgb3），通过调节细胞外基质参与表皮的平衡，是体内基于 EV 的细胞间通信的重要介质。我们首先证明了健康的真皮成纤维细胞会产生和分泌具有外泌体小EVs（sEVs）特征的EVs。我们发现，CD98hc（Itgb1 共受体）存在于 sEVs 表面，并在质膜上转移和稳定。转移的复合物在体外和体内都对受体细胞起作用。事实上，用 WT 细胞（而非 KO 细胞）的 sEVs 处理可挽救体外观察到的 CD98hc KO 皮肤成纤维细胞或角质形成细胞的迁移缺陷。此外，在伤口愈合受损的小鼠模型（表现出愈合缺陷的表皮 CD98hc KO 小鼠和老年小鼠）的伤口边缘注射 sEV 可改善体内伤口的闭合。从 sEVs 中转移的 CD98hc 复合物在注射后至少 7 天仍保持稳定。因此，我们的研究结果表明，使用含有整合素共受体 CD98hc 的 sEVs 在体内治疗可改善多种皮肤疾病。
{"title":"Functional transfer of integrin co-receptor CD98hc by small extracellular vesicles improves wound healing in vivo","authors":"Floriane S. Tissot , Soline Estrach , Laetitia Seguin , Laurence Cailleteau , Ayelet Levy , Daniel Aberdam , Chloé C. Féral","doi":"10.1016/j.matbio.2024.12.006","DOIUrl":"10.1016/j.matbio.2024.12.006","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) mediate intercellular communication. EVs are composed of a lipid bilayer and contain cytosolic proteins and RNAs. Studies highlight EVs striking functions in cell-cell crosstalk. Here, we found that small EVs can transfer functional signaling molecules through their lipid bilayer and participate in skin homeostasis. We identified a transmembrane protein CD98hc (a.k.a. SLC3A2), an integrin co-receptor (Itgb1 and Itgb3), implicated in epidermis homeostasis via its capacity in regulating extracellular matrix, as an important mediator of EV-based intercellular communication <em>in vivo</em>. We first demonstrated that healthy dermal fibroblasts produced and secreted EVs bearing characteristic of exosome-like small EVs (sEVs). We show that CD98hc, Itgb1 co-receptor, is present at the surface of sEVs, transferred and stabilized at the plasma membrane. The transferred complex is functional on recipient cells both <em>in vitro</em> and <em>in vivo</em>. Indeed, treatment with sEVs from WT, but not KO cells rescued migratory defects observed either in CD98hc KO dermal fibroblasts or in keratinocytes <em>in vitro</em>. Furthermore, injection of sEVs at the margins of wound in impaired wound healing mouse models (epidermal CD98hc KO mice exhibiting healing defect and elderly mice) improved wound closure <em>in vivo</em>. CD98hc complex transferred from sEVs remained stabilized at least 7 days after injection. Thus, our findings reveal that <em>in vivo</em> treatment with sEVs containing integrin co-receptor CD98hc could improve multiple skin afflictions.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 99-105"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.004
Rieke Schleinhege , Ilka Neumann , Andrea Oeckinghaus , Albrecht Schwab , Zoltán Pethő
Rationale
Pancreatic stellate cells (PSCs) produce a collagen-rich connective tissue in chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Ca2+-permeable ion channels such as ORAI1 are known to affect PSC proliferation and myofibroblastic phenotype. However, it is unknown whether these channels play a role in collagen secretion.
Methods
Using the PSC cell line PS-1, we characterized their cell-derived matrices using staining, mass spectroscopy, and cell migration assays. We developed and validated a high-throughput in vitro fibrosis assay to rapidly determine collagen quantity either with Sirius Red or, in the optimized version, with the collagen-binding peptide CNA-35-tdTomato. We assessed collagen deposition upon stimulating cells with transforming growth factor β1 (TGF-β1) and/or vitamin C without or with ORAI1 modulation. Orai1 expression was assessed by immunohistochemistry in the fibrotic tumor tissue of a murine PDAC model (KPfC).
Results
We found that TGF-β1 and vitamin C promote collagen deposition from PSCs. We used small interfering RNA (siRNA) and the inhibitor Synta-66 to demonstrate that ORAI1 regulates collagen secretion of PSCs but not NIH-3T3 fibroblasts. Physiological levels of vitamin C induce a drastic increase of the intracellular [Ca2+] in PSCs, with Synta-66 inhibiting Ca2+ influx. Lastly, we revealed Orai1 expression in cancer-associated fibroblasts (CAFs) in murine PDAC (KPfC) samples.
Conclusion
In conclusion, our study introduces a robust in vitro assay for fibrosis and identifies ORAI1 as being engaged in PSC-driven fibrosis.
{"title":"A CNA-35-based high-throughput fibrosis assay reveals ORAI1 as a regulator of collagen release from pancreatic stellate cells","authors":"Rieke Schleinhege , Ilka Neumann , Andrea Oeckinghaus , Albrecht Schwab , Zoltán Pethő","doi":"10.1016/j.matbio.2024.12.004","DOIUrl":"10.1016/j.matbio.2024.12.004","url":null,"abstract":"<div><h3>Rationale</h3><div>Pancreatic stellate cells (PSCs) produce a collagen-rich connective tissue in chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Ca<sup>2+</sup>-permeable ion channels such as ORAI1 are known to affect PSC proliferation and myofibroblastic phenotype. However, it is unknown whether these channels play a role in collagen secretion.</div></div><div><h3>Methods</h3><div>Using the PSC cell line PS-1, we characterized their cell-derived matrices using staining, mass spectroscopy, and cell migration assays. We developed and validated a high-throughput <em>in vitro</em> fibrosis assay to rapidly determine collagen quantity either with Sirius Red or, in the optimized version, with the collagen-binding peptide CNA-35-tdTomato. We assessed collagen deposition upon stimulating cells with transforming growth factor β1 (TGF-β1) and/or vitamin C without or with ORAI1 modulation. Orai1 expression was assessed by immunohistochemistry in the fibrotic tumor tissue of a murine PDAC model (KPfC).</div></div><div><h3>Results</h3><div>We found that TGF-β1 and vitamin C promote collagen deposition from PSCs. We used small interfering RNA (siRNA) and the inhibitor Synta-66 to demonstrate that ORAI1 regulates collagen secretion of PSCs but not NIH-3T3 fibroblasts. Physiological levels of vitamin C induce a drastic increase of the intracellular [Ca<sup>2+</sup>] in PSCs, with Synta-66 inhibiting Ca<sup>2+</sup> influx. Lastly, we revealed Orai1 expression in cancer-associated fibroblasts (CAFs) in murine PDAC (KPfC) samples.</div></div><div><h3>Conclusion</h3><div>In conclusion, our study introduces a robust <em>in vitro</em> assay for fibrosis and identifies ORAI1 as being engaged in PSC-driven fibrosis.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 70-86"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.11.006
ASM Sakhawat Hossain , Maria Thea Rane Dela Cruz Clarin , Kenichi Kimura , George Biggin , Yuki Taga , Koichiro Uto , Ayana Yamagishi , Eri Motoyama , Narenmandula , Kazunori Mizuno , Chikashi Nakamura , Keiichi Asano , Sumio Ohtsuki , Tomoyuki Nakamura , Sachiko Kanki , Clair Baldock , Erna Raja , Hiromi Yanagisawa
Fibrillin-1, an extracellular matrix (ECM) protein encoded by the FBN1 gene, serves as a microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Aside from causing Marfan syndrome, some mutations in FBN1 result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we describe a tight skin phenotype in the Fbn1G234D/G234D mice carrying a corresponding variant of FBN1 in the hybrid1 domain that was identified in a patient with familial aortic dissection. Unlike scleroderma, skin thickness and collagen fiber abundance do not change in the Fbn1G234D/G234D mutant skin. Instead, increased collagen cross-links were observed. In addition, short elastic fibers were sparsely located underneath the panniculus muscle layer, and an abundance of thin, aberrant elastic fibers was increased within the subcutaneous fascia, which may have tightened skin attachment to the underlying skeletal muscle. Structurally, Fbn1G234D/G234D microfibrils have a disrupted shoulder region that shares similarities with hybrid1 deletion mutant microfibrils. We then demonstrate the consequence of fibrillin-1 G234D mutation on dermal fibroblast functions. Mutant primary fibroblasts produce fewer elastic fibers, exhibit slower migration and increased cell stiffness. Moreover, secretome from mutant fibroblasts are marked by enhanced secretion of ECM, ECM-modifying enzymes, proteoglycans and cytokines, which are pro-tissue repair/fibrogenic. The transcriptome of mutant fibroblasts displays an increased expression of myogenic developmental and immune-related genes. Our study proposes that imbalanced ECM homeostasis due to a fibrillin-1 G234D mutation impacts fibroblast properties with potential ramifications on skin function.
{"title":"Fibrillin-1 G234D mutation in the hybrid1 domain causes tight skin associated with dysregulated elastogenesis and increased collagen cross-linking in mice","authors":"ASM Sakhawat Hossain , Maria Thea Rane Dela Cruz Clarin , Kenichi Kimura , George Biggin , Yuki Taga , Koichiro Uto , Ayana Yamagishi , Eri Motoyama , Narenmandula , Kazunori Mizuno , Chikashi Nakamura , Keiichi Asano , Sumio Ohtsuki , Tomoyuki Nakamura , Sachiko Kanki , Clair Baldock , Erna Raja , Hiromi Yanagisawa","doi":"10.1016/j.matbio.2024.11.006","DOIUrl":"10.1016/j.matbio.2024.11.006","url":null,"abstract":"<div><div>Fibrillin-1, an extracellular matrix (ECM) protein encoded by the <em>FBN1</em> gene, serves as a microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Aside from causing Marfan syndrome, some mutations in <em>FBN1</em> result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we describe a tight skin phenotype in the <em>Fbn1</em><sup>G234D/G234D</sup> mice carrying a corresponding variant of <em>FBN1</em> in the hybrid1 domain that was identified in a patient with familial aortic dissection. Unlike scleroderma, skin thickness and collagen fiber abundance do not change in the <em>Fbn1</em><sup>G234D/G234D</sup> mutant skin. Instead, increased collagen cross-links were observed. In addition, short elastic fibers were sparsely located underneath the panniculus muscle layer, and an abundance of thin, aberrant elastic fibers was increased within the subcutaneous fascia, which may have tightened skin attachment to the underlying skeletal muscle. Structurally, <em>Fbn1</em><sup>G234D/G234D</sup> microfibrils have a disrupted shoulder region that shares similarities with hybrid1 deletion mutant microfibrils. We then demonstrate the consequence of fibrillin-1 G234D mutation on dermal fibroblast functions. Mutant primary fibroblasts produce fewer elastic fibers, exhibit slower migration and increased cell stiffness. Moreover, secretome from mutant fibroblasts are marked by enhanced secretion of ECM, ECM-modifying enzymes, proteoglycans and cytokines, which are pro-tissue repair/fibrogenic. The transcriptome of mutant fibroblasts displays an increased expression of myogenic developmental and immune-related genes. Our study proposes that imbalanced ECM homeostasis due to a fibrillin-1 G234D mutation impacts fibroblast properties with potential ramifications on skin function.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 24-38"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.009
Shinhye Min , Bohee Jang , Ji-Hye Yun , Hyeonju Yang , Jee Young Sung , Ga-Eun Lim , Yong-Nyun Kim , Weontae Lee , Eok-Soo Oh
Disrupting the interaction between matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) can yield anticancer effects in colon cancer cells. Here, a single-chain variable fragment (scFv) targeting the pro-domain of MMP-7 was generated as a potential candidate anticancer agent. Among the generated scFvs, those designated 1B7 and 1C3 showed the strongest abilities to inhibit the ability of MMP-7 pro-domain to directly interact with SDC-2 in vitro and decrease the cancer activities of human HT29 colon adenocarcinoma cells. Consistently, 1B7 and 1C3 inhibited the cell-surface localization of pro-MMP-7, reduced the gelatinolytic activity of MMP-7, and suppressed the cancer activities of metastatic HCT116 human colon carcinoma cells. Notably, 1B7 inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a mouse model. Compared to 1B7, the 1B7-Fc fusion antibody showed better anti-tumorigenic activity against HCT116 cells in culture and a syngeneic mouse model. Together, these data suggest that 1B7-Fc exerts anticancer effects by interfering with the interaction of MMP-7 and SDC-2 and could be a promising therapeutic antibody for colon cancer.
{"title":"Anticancer effect of a single-chain variable fragment against pro-matrix metalloproteinase-7 in colon cancer","authors":"Shinhye Min , Bohee Jang , Ji-Hye Yun , Hyeonju Yang , Jee Young Sung , Ga-Eun Lim , Yong-Nyun Kim , Weontae Lee , Eok-Soo Oh","doi":"10.1016/j.matbio.2024.12.009","DOIUrl":"10.1016/j.matbio.2024.12.009","url":null,"abstract":"<div><div>Disrupting the interaction between matrix metalloproteinase-7 (MMP-7) and syndecan-2 (SDC-2) can yield anticancer effects in colon cancer cells. Here, a single-chain variable fragment (scFv) targeting the pro-domain of MMP-7 was generated as a potential candidate anticancer agent. Among the generated scFvs, those designated 1B7 and 1C3 showed the strongest abilities to inhibit the ability of MMP-7 pro-domain to directly interact with SDC-2 in vitro and decrease the cancer activities of human HT29 colon adenocarcinoma cells. Consistently, 1B7 and 1C3 inhibited the cell-surface localization of pro-MMP-7, reduced the gelatinolytic activity of MMP-7, and suppressed the cancer activities of metastatic HCT116 human colon carcinoma cells. Notably, 1B7 inhibited the primary tumor growth and lung metastasis of CT26 mouse colon cancer cells in a mouse model. Compared to 1B7, the 1B7-Fc fusion antibody showed better anti-tumorigenic activity against HCT116 cells in culture and a syngeneic mouse model. Together, these data suggest that 1B7-Fc exerts anticancer effects by interfering with the interaction of MMP-7 and SDC-2 and could be a promising therapeutic antibody for colon cancer.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 125-134"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142889269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.003
Nibedita Dalpati, Shubham Kumar Rai, Prerna Sharma, Pranita P. Sarangi
Integrins, a group of transmembrane receptors, play a crucial role in mediating the interactions between cells and extracellular matrix (ECM) proteins. The intracellular signaling initiated by these cell-matrix interactions in leukocytes mediates many essential cellular processes such as survival, migration, metabolism, and other immunological functions. Macrophages, as phagocytes, participate in both proinflammatory and anti-inflammatory processes, including progression. Numerous reports have shown that the integrin-regulated secretome, comprising cytokines, chemokines, growth factors, proteases, and other bioactive molecules, is a crucial modulator of macrophage functions in tumors, significantly influencing macrophage programming and reprogramming within the tumor microenvironment (TME) in addition to driving their step-by-step entry process into tumor tissue spaces. Importantly, studies have demonstrated a pivotal role for integrin receptor-mediated secretome and associated signaling pathways in functional reprogramming from anti-tumorigenic to pro-tumorigenic phenotype in tumor-associated macrophages (TAMs). In this comprehensive review, we have provided an in-depth analysis of the latest findings of various key pathways, mediators, and signaling cascades associated with integrin-driven polarization of macrophages in tumors. This manuscript will provide an updated understanding of the modulation of inflammatory monocytes/ macrophages and TAMs by integrin-driven secretory pathways in various functions such as migration, differentiation, and their role in tumor progression, angiogenesis, and metastasis.
{"title":"Integrins and integrin-driven secretory pathways as multi-dimensional regulators of tumor-associated macrophage recruitment and reprogramming in tumor microenvironment","authors":"Nibedita Dalpati, Shubham Kumar Rai, Prerna Sharma, Pranita P. Sarangi","doi":"10.1016/j.matbio.2024.12.003","DOIUrl":"10.1016/j.matbio.2024.12.003","url":null,"abstract":"<div><div>Integrins, a group of transmembrane receptors, play a crucial role in mediating the interactions between cells and extracellular matrix (ECM) proteins. The intracellular signaling initiated by these cell-matrix interactions in leukocytes mediates many essential cellular processes such as survival, migration, metabolism, and other immunological functions. Macrophages, as phagocytes, participate in both proinflammatory and anti-inflammatory processes, including progression. Numerous reports have shown that the integrin-regulated secretome, comprising cytokines, chemokines, growth factors, proteases, and other bioactive molecules, is a crucial modulator of macrophage functions in tumors, significantly influencing macrophage programming and reprogramming within the tumor microenvironment (TME) in addition to driving their step-by-step entry process into tumor tissue spaces. Importantly, studies have demonstrated a pivotal role for integrin receptor-mediated secretome and associated signaling pathways in functional reprogramming from anti-tumorigenic to pro-tumorigenic phenotype in tumor-associated macrophages (TAMs). In this comprehensive review, we have provided an in-depth analysis of the latest findings of various key pathways, mediators, and signaling cascades associated with integrin-driven polarization of macrophages in tumors. This manuscript will provide an updated understanding of the modulation of inflammatory monocytes/ macrophages and TAMs by integrin-driven secretory pathways in various functions such as migration, differentiation, and their role in tumor progression, angiogenesis, and metastasis.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 55-69"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.008
Irene Torre-Cea, Patricia Berlana-Galán, Elena Guerra-Paes, Daniel Cáceres-Calle, Iván Carrera-Aguado, Laura Marcos-Zazo, Fernando Sánchez-Juanes , José M. Muñoz-Félix
The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components—collagens, fibronectin, and laminin—and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases.
{"title":"Basement membranes in lung metastasis growth and progression","authors":"Irene Torre-Cea, Patricia Berlana-Galán, Elena Guerra-Paes, Daniel Cáceres-Calle, Iván Carrera-Aguado, Laura Marcos-Zazo, Fernando Sánchez-Juanes , José M. Muñoz-Félix","doi":"10.1016/j.matbio.2024.12.008","DOIUrl":"10.1016/j.matbio.2024.12.008","url":null,"abstract":"<div><div>The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components—collagens, fibronectin, and laminin—and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 135-152"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.002
Sonal Gahlawat , Jan Siess , Natalie Losada , Jennifer Timm , Vikas Nanda , David I. Shreiber
Vascular Ehlers-Danlos syndrome (vEDS) arises from mutations in collagen-III, a major structural component of the extracellular matrix (ECM) in vascularized tissues, including blood vessels. Fibrillar collagens form a triple-helix that is characterized by a canonical (Gly-X-Y)n sequence. The substitution of another amino acid for Gly within this conserved repeating sequence is associated with several hereditary connective tissue disorders, including vEDS. The clinical severity of vEDS depends on the identity of the substituted amino acid and its location. In this study, we engineered recombinant bacterial collagen-like proteins (CLPs) with previously reported Gly→X (X=Ser or Arg) vEDS substitutions within the integrin-binding site. Employing a combination of biophysical techniques, enzymatic digestion assays, integrin binding affinity assays, and computational modeling, we assessed the impact of Gly→X substitutions on structure, stability, function, and mechanical properties. While constructs with Ser or Arg substitutions maintained a triple-helix structure, Arg substitution significantly reduced global thermal stability, heightened susceptibility to trypsin digestion, and altered integrin α2-inserted (α2I) domain binding. Molecular dynamics (MD) simulations also demonstrated distinct effects of different Gly substitutions on the triple-helix structure - Arg substitutions induced notable bulging at the substitution site and disrupted interchain hydrogen bonds compared to Ser substitutions. Additionally, steered MD simulations revealed that Arg substitution led to a significant decrease in the Young's modulus of the triple-helix. Bacterial CLPs have proved to be a powerful model for studying the underlying mechanisms of vEDS-causing mutations in collagen-III. Serine and arginine substitutions differentially perturb cell-matrix interactions and ECM in a manner consistent with clinical vEDS severity.
{"title":"Impact of vascular Ehlers-Danlos Syndrome-associated Gly substitutions on structure, function, and mechanics using bacterial collagen","authors":"Sonal Gahlawat , Jan Siess , Natalie Losada , Jennifer Timm , Vikas Nanda , David I. Shreiber","doi":"10.1016/j.matbio.2024.12.002","DOIUrl":"10.1016/j.matbio.2024.12.002","url":null,"abstract":"<div><div>Vascular Ehlers-Danlos syndrome (vEDS) arises from mutations in collagen-III, a major structural component of the extracellular matrix (ECM) in vascularized tissues, including blood vessels. Fibrillar collagens form a triple-helix that is characterized by a canonical (Gly-X-Y)<sub>n</sub> sequence. The substitution of another amino acid for Gly within this conserved repeating sequence is associated with several hereditary connective tissue disorders, including vEDS. The clinical severity of vEDS depends on the identity of the substituted amino acid and its location. In this study, we engineered recombinant bacterial collagen-like proteins (CLPs) with previously reported Gly→X (X=Ser or Arg) vEDS substitutions within the integrin-binding site. Employing a combination of biophysical techniques, enzymatic digestion assays, integrin binding affinity assays, and computational modeling, we assessed the impact of Gly→X substitutions on structure, stability, function, and mechanical properties. While constructs with Ser or Arg substitutions maintained a triple-helix structure, Arg substitution significantly reduced global thermal stability, heightened susceptibility to trypsin digestion, and altered integrin α2-inserted (α2I) domain binding. Molecular dynamics (MD) simulations also demonstrated distinct effects of different Gly substitutions on the triple-helix structure - Arg substitutions induced notable bulging at the substitution site and disrupted interchain hydrogen bonds compared to Ser substitutions. Additionally, steered MD simulations revealed that Arg substitution led to a significant decrease in the Young's modulus of the triple-helix. Bacterial CLPs have proved to be a powerful model for studying the underlying mechanisms of vEDS-causing mutations in collagen-III. Serine and arginine substitutions differentially perturb cell-matrix interactions and ECM in a manner consistent with clinical vEDS severity.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 87-98"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.matbio.2024.12.007
Daniel Sloseris, Nancy R. Forde
Advanced Glycation End Products (AGEs) are the end result of the irreversible, non-enzymatic glycation of proteins by reducing sugars. These chemical modifications accumulate with age and have been associated with various age-related and diabetic complications. AGEs predominantly accumulate on proteins with slow turnover rates, of which collagen is a prime example. Glycation has been associated with tissue stiffening and reduced collagen fibril remodelling. In this study, we investigate the effects of glycation on the stability of type I collagen, its molecular-level mechanics and its ability to perform its physiological role of self-assembly. Collagen AGEing is induced in vitro by incubation with ribose. We confirm and assess glycation using fluorescence measurements and changes in collagen’s electrophoretic mobility. Susceptibility to trypsin digestion and circular dichroism (CD) spectroscopy are used to probe changes in collagen’s triple helical stability, revealing decreased stability due to glycation. Atomic Force Microscopy (AFM) imaging is used to quantify how AGEing affects collagen flexibility, where we find molecular-scale stiffening. Finally we use microscopy to show that glycated collagen molecules are unable to self-assemble into fibrils. These findings shed light on the molecular mechanisms underlying AGE-induced tissue changes, offering insight into how glycation modifies protein structure and stability.
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