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TNC Reduces EC Survival and Proliferation (A–F) MTS assay for HUVECs (A and D), BAECs (B and E), and pericytes (C and F) upon plating on the indicated ECM molecules (1–2 mg/cm 2 ) (A–C) or on CDM derived from TNC KO (TNCÀ) or WT MEFs (TNC+) (D–F) for up to 72 hr. (A–C) Values are mean ± SEM from five independent experiments with five replicates. (D–F) Values are mean ± SEM in HUVECs (five independent experiments with five or six replicates), BAECs (three independent experiments with three replicates), and pericytes (four independent experiments with six replicates). (G and H) Assessment of HUVEC apoptosis after 72 hr upon growth on ECM-coated wells (G) or CDM containing (TNC+) or lacking TNC (TNCÀ). Representative images of IF staining for cleaved caspase-3 (red) and nuclei with DAPI (blue); scale bar, 100 mm (H). Values are mean ± SEM from three independent experiments with four replicates. Four random fields were quantified per replicate. (I) Assessment of HUVEC proliferation after 48 hr upon growth on ECM-coated wells. Values are mean ± SEM of three independent experiments with six replicates. See also Figure S3.
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High expression of the extracellular matrix component tenascin-C in the tumor microenvironment correlates with decreased patient survival. Tenascin-C promotes cancer progression and a disrupted tumor vasculature through an unclear mechanism. Here, we examine the angiomodulatory role of tenascin-C. We find that direct contact of endothelial cells wi...
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... also investigated if and how TNC affected EC proliferation using an MTS incorporation assay. Whereas HUVECs and BAECs proliferated on FN and Col I over 3 days, their growth only slightly increased on TNC in the same time frame, demon- strating an inhibitory effect of TNC ( Figures 3A and 3B) that was dose dependent ( Figure S3A). In contrast to ECs, despite delayed cell adhesion on TNC, the growth of pericytes over time was unaffected by TNC ( Figure 3C). ...
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... also investigated if and how TNC affected EC proliferation using an MTS incorporation assay. Whereas HUVECs and BAECs proliferated on FN and Col I over 3 days, their growth only slightly increased on TNC in the same time frame, demon- strating an inhibitory effect of TNC ( Figures 3A and 3B) that was dose dependent ( Figure S3A). In contrast to ECs, despite delayed cell adhesion on TNC, the growth of pericytes over time was unaffected by TNC ( Figure 3C). ...
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... HUVECs and BAECs proliferated on FN and Col I over 3 days, their growth only slightly increased on TNC in the same time frame, demon- strating an inhibitory effect of TNC ( Figures 3A and 3B) that was dose dependent ( Figure S3A). In contrast to ECs, despite delayed cell adhesion on TNC, the growth of pericytes over time was unaffected by TNC ( Figure 3C). ...
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... over, 3D models exhibit properties such as mechanical compli- ance and immobilization of growth factors that are closer to the complexity found in tissues ( Beacham et al., 2007). Here, we generated a 3D cell-derived matrix (CDM) as described pre- viously ( Beacham et al., 2007) ( Figure S3B) that was assembled by mouse embryonic fibroblasts (MEFs) derived from TNC KO (TNCÀ) or TNC WT (TNC+) mice. We confirmed that CDM from TNC KO MEFs was devoid of TNC and that both CDMs pre- sented a similar fibrillar ECM network comprising FN, periostin, and Col I ( Figure S3C). ...
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... we generated a 3D cell-derived matrix (CDM) as described pre- viously ( Beacham et al., 2007) ( Figure S3B) that was assembled by mouse embryonic fibroblasts (MEFs) derived from TNC KO (TNCÀ) or TNC WT (TNC+) mice. We confirmed that CDM from TNC KO MEFs was devoid of TNC and that both CDMs pre- sented a similar fibrillar ECM network comprising FN, periostin, and Col I ( Figure S3C). Growth of both EC types tested (HUVECs and BAECs) was higher on TNC -deficient CDM than on the CDM containing the TNC protein ( Figures 3D and 3E). ...
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... confirmed that CDM from TNC KO MEFs was devoid of TNC and that both CDMs pre- sented a similar fibrillar ECM network comprising FN, periostin, and Col I ( Figure S3C). Growth of both EC types tested (HUVECs and BAECs) was higher on TNC -deficient CDM than on the CDM containing the TNC protein ( Figures 3D and 3E). Similarly BAEC growth was reduced on CDM generated by CAFs with TNC knockdown (KD) (shTNC) when compared with control (shCTRL) cells ( Figure S3D), whereas pericyte growth was unaffected ( Figure 3F). ...
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... of both EC types tested (HUVECs and BAECs) was higher on TNC -deficient CDM than on the CDM containing the TNC protein ( Figures 3D and 3E). Similarly BAEC growth was reduced on CDM generated by CAFs with TNC knockdown (KD) (shTNC) when compared with control (shCTRL) cells ( Figure S3D), whereas pericyte growth was unaffected ( Figure 3F). These findings recapitulate the inhibitory effect of TNC on the growth of ECs on a 2D TNC substratum. ...
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... of both EC types tested (HUVECs and BAECs) was higher on TNC -deficient CDM than on the CDM containing the TNC protein ( Figures 3D and 3E). Similarly BAEC growth was reduced on CDM generated by CAFs with TNC knockdown (KD) (shTNC) when compared with control (shCTRL) cells ( Figure S3D), whereas pericyte growth was unaffected ( Figure 3F). These findings recapitulate the inhibitory effect of TNC on the growth of ECs on a 2D TNC substratum. ...
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... of cell growth by TNC could depend on an altered balance of survival and proliferation, which we tested by plating HUVECs on either purified ECM coatings or CDM. Indeed, TNC- containing substrata increased EC apoptosis, as illustrated by the increased number of cleaved-caspase-3-positive nuclei in the presence of TNC ( Figures 3G and 3H). Assessing prolifera- tion by bromodeoxyuridine (BrdU) incorporation revealed a reduction on TNC in comparison to FN and Col I ( Figure 3I). ...
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... TNC- containing substrata increased EC apoptosis, as illustrated by the increased number of cleaved-caspase-3-positive nuclei in the presence of TNC ( Figures 3G and 3H). Assessing prolifera- tion by bromodeoxyuridine (BrdU) incorporation revealed a reduction on TNC in comparison to FN and Col I ( Figure 3I). Thus, ECs exposed to TNC are prone to apoptosis and show a reduced proliferation rate. ...
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... could have an impact on endo- thelium function, which we tested in an in vitro Boyden chamber permeability assay. We observed that the TNC substratum increased dextran-FITC diffusion across the endothelial mono- layer over that of the other ECM coatings ( Figure S3E), suggest- ing that TNC may alter endothelial monolayer integrity in vitro. ...
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Simple Summary
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B lymphocytes in the peripheral components of the immune system. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur. In the bone marrow and secondary lymphoid tissues, the trafficking, survival, and proli...
Citations
... An exclusive core localisation demonstrates a relationship of increased Tenascin-C levels under hypoxic conditions, indicating a potential rise in hypoxia-related drug resistance. Tenascin-C is known to promote survival and invasion by regulating the expression of proangiogenic factors such as vascular endothelial growth factor (VEGF) [79]. The regulation of angiogenesis could play a key part in a localised tumour-core-specific drug resistance mechanism, demonstrating the role of Tenascin-C in the promotion of survival and expression of proangiogenic factors. ...
A multimodal mass spectrometry imaging (MSI) approach was used to investigate the chemotherapy drug-induced response of a Multicellular Tumour Spheroid (MCTS) 3D cell culture model of osteosarcoma (OS). The work addresses the critical demand for enhanced translatable early drug discovery approaches by demonstrating a robust spatially resolved molecular distribution analysis in tumour models following chemotherapeutic intervention. Advanced high-resolution techniques were employed, including desorption electrospray ionisation (DESI) mass spectrometry imaging (MSI), to assess the interplay between metabolic and cellular pathways in response to chemotherapeutic intervention. Endogenous metabolite distributions of the human OS tumour models were complemented with subcellularly resolved protein localisation by the detection of metal-tagged antibodies using Imaging Mass Cytometry (IMC). The first application of matrix-assisted laser desorption ionization–immunohistochemistry (MALDI-IHC) of 3D cell culture models is reported here. Protein localisation and expression following an acute dosage of the chemotherapy drug doxorubicin demonstrated novel indications for mechanisms of region-specific tumour survival and cell-cycle-specific drug-induced responses. Previously unknown doxorubicin-induced metabolite upregulation was revealed by DESI-MSI of MCTSs, which may be used to inform mechanisms of chemotherapeutic resistance. The demonstration of specific tumour survival mechanisms that are characteristic of those reported for in vivo tumours has underscored the increasing value of this approach as a tool to investigate drug resistance.
... TNC and FN ED-B are significant components of the angiogenic vasculature in tumors, but are scarce in quiescent adult vessels. TNC is associated with an increase in leaky blood vessels in tumors (Saupe et al., 2013;Rupp et al., 2016;Sun et al., 2019). TNC deposition is also present in the peripheral margins of invasive carcinomas (Giuffrida et al., 2004;Nagaharu et al., 2011). ...
The extracellular matrix (ECM) is a complex network of proteins and glycans, dynamically remodeled and specifically tailored to the structure/function of each organ. The malignant transformation of cancer cells is determined by both cell intrinsic properties, such as mutations, and extrinsic variables, such as the mixture of surrounding cells in the tumor microenvironment and the biophysics of the ECM. During cancer progression, the ECM undergoes extensive remodeling, characterized by disruption of the basal lamina, vascular endothelial cell invasion, and development of fibrosis in and around the tumor cells resulting in increased tissue stiffness. This enhanced rigidity leads to aberrant mechanotransduction and further malignant transformation potentiating the de-differentiation, proliferation and invasion of tumor cells. Interestingly, this fibrotic microenvironment is primarily secreted and assembled by non-cancerous cells. Among them, the cancer-associated fibroblasts (CAFs) play a central role. CAFs massively produce fibronectin together with type I collagen. This review delves into the primary interactions and signaling pathways through which fibronectin can support tumorigenesis and metastasis, aiming to provide critical molecular insights for better therapy response prediction.
... CAFs play a pivotal role in producing crucial matrisome components necessary for vascular formation [81]. These components encompass various molecules like TNC, known to prompt pro-angiogenic signaling [82]; CYR61, which facilitates adhesion, migration, and proliferation of ECs [83]; and OPN, that induces angiogenesis through activation of PI3K and ERK in ECs [84]. Additionally, CAFs exhibit increased expression of multiple MMPs capable of degrading ECM, releasing stored soluble factors, and thereby altering the signaling properties of the TME and affecting angiogenesis. ...
Neoplastic progression involves complex interactions between cancer cells and the surrounding stromal milieu, fostering microenvironments that crucially drive tumor progression and dissemination. Of these stromal constituents, cancer-associated fibroblasts (CAFs) emerge as predominant inhabitants within the tumor microenvironment (TME), actively shaping multiple facets of tumorigenesis, including cancer cell proliferation, invasiveness, and immune evasion. Notably, CAFs also orchestrate the production of pro-angiogenic factors, fueling neovascularization to sustain the metabolic demands of proliferating cancer cells. Moreover, CAFs may also directly or indirectly affect endothelial cell behavior and vascular architecture, which may impact in tumor progression and responses to anti-cancer interventions. Conversely, tumor endothelial cells (TECs) exhibit a corrupted state that has been shown to affect cancer cell growth and inflammation. Both CAFs and TECs are emerging as pivotal regulators of the TME, engaging in multifaceted biological processes that significantly impact cancer progression, dissemination, and therapeutic responses. Yet, the intricate interplay between these stromal components and the orchestrated functions of each cell type remains incompletely elucidated. In this review, we summarize the current understanding of the dynamic interrelationships between CAFs and TECs, discussing the challenges and prospects for leveraging their interactions towards therapeutic advancements in cancer.
... The mechanical properties of the ECM also contribute to modulating these angiogenic processes (Kretschmer et al., 2021). Therefore, ECM molecules can have both pro-and antiangiogenic effects (Petrik et al., 2010;Rupp et al., 2016). ...
... Certain ECM components are already well known to modulate GBM angiogenesis, such as tenascin C (Zagzag et al., 1995;Behrem et al., 2005;Rupp et al., 2016), collagens I, IV and VI (Yunker et al., 2008;Mammoto et al., 2013), hyaluronan (HA) (Liu et al., 1996), laminin (Ljubimova et al., 2006), versican and fibronectin (Yang and Yee, 2013). Due to the importance of ECM and vascularity to the GBM aggressiveness and the dual angiogenic effects of ECM components, we proposed to study the influence of GBM ECM in EC proliferation, branching and ECM expression with or without GBM influence. ...
Glioblastomas (GBM) are aggressive tumors, characterized by heterogeneity, high proliferation and infiltration, resistance to treatments, and abundant vasculature. Angiogenesis, the formation of new vessels from pre-existing ones, involves endothelial cells (EC) migrating and proliferating to form new tubes. Various extracellular matrix (ECM) molecules can modulate EC survival, migration, and proliferation. In this study, we cultured human brain EC (HBMEC) on GBM-derived ECM and found that GBM ECM inhibited EC proliferation and modulated the branching process (average vessel length, number of junctions, and vessel endpoints) compared to the HBMEC ECM control. Through in silico analysis, we investigated whether GBM influences the expression of ECM molecules in EC and which of these molecules directly impact the overall survival (OS) of GBM patients. We observed increased expression of collagen alpha chains (COL5A3, 6A1, 22A1, and 27A1), laminin alpha and beta chains (LAMA1 and B1), fibulins (FBLN1 and 2), metalloproteinase (MMP)-9, hyaluronan synthase (HAS)1, integrin alpha chain (ITGA)3, transforming growth factor beta-1 (TGFB1), and wingless-related integration site (Wnt)-9B in EC influenced by GBM compared to normal brain EC. Furthermore, our study demonstrated that the expression of these ECM molecules, along with neurocan (NCAN), directly influenced the OS of GBM patients. In conclusion, this study identifies both established and novel ECM molecules that can regulate GBM angiogenesis and highlights NCAN, COL22A1, and COL27A1 as potential new biomarkers for GBM prognosis.
... Conversely, typical fibrillar ECM proteins constitute minor components of the brain ECM, concentrated in the perivascular niche in the healthy brain. Gliomagenesis is associated with major alterations in the expression pattern of ECM proteins [14,[42][43][44]. The literature evidence regarding COLI expression in GBM is rather scarce and contradictory. ...
Purpose
Gliomagenesis is associated with changes in extracellular matrix (ECM) composition. We investigate the role of fibroblast activation protein-positive (FAP+) pericyte-like cells in ECM alterations in glioblastoma and their impact on glioma cells.
Methods
Bioinformatic analysis, immunohistochemistry, and ELISA were used to evaluate the expression of ECM proteins and FAP. FAP + pericyte-like cells were isolated from human glioblastomas, ECM production was quantified by ELISA and using mass spectrometry analysis of 3D matrices. Haptotaxis and focal adhesion kinase (FAK) signaling activation assays were performed to assess the influence of the ECM on glioma cells.
Results
Higher FAP expression was associated with elevated levels of collagen I and fibronectin in glioblastoma. FAP + pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in glioblastoma. Mass spectrometry revealed that in contrast to glioma cells, 3D matrices produced by FAP + pericyte-like cells were rich in collagen I and fibronectin and contained several key basement membrane proteins. ECM produced by FAP + pericyte-like cells enhanced migration and adhesion of glioma cells, including glioma stem-like cells, and promoted focal adhesion kinase (FAK) signaling.
Conclusion
This study establishes FAP + pericyte-like cells as crucial producers of an ECM rich in collagen I and fibronectin in glioblastoma microenvironment. Such ECM triggers FAK activation and facilitates the dissemination of glioma cells. Our data provide new insights into the mechanisms underlying gliomagenesis.
... 23 Dysregulation of ECM connector molecules has been implicated in carcinogenesis. 3,[45][46][47][48] Bioinformatics studies have recently identified MATN3 as a prognostic marker for osteosarcoma and gastric F I G U R E 5 MATN3 promotes gastric cancer cell invasion via the LC and CC domains. (A, B) GCF-1 cells were infected with lentivirus expressing the indicated MATN3 constructs, co-cultured with gastric cancer cells (Green labeled), and then applied for Transwell invasion assays. ...
Cancer‐associated fibroblast (CAF) has emerged as a key contributor to the remodeling of tumor microenvironment through the expression and secretion of extracellular matrix (ECM) proteins, thereby promoting carcinogenesis. However, the precise contribution of ECM proteins from CAFs to gastric carcinogenesis remains poorly understood. In this study, we find that matrilin‐3 (MATN3), an upregulated ECM protein associated with poorer prognosis in gastric cancer patients, originates from CAFs in gastric cancer tissues. Ectopic expression of MATN3 in CAFs significantly promotes the invasion of gastric cancer cells, which can be attenuated by neutralizing MATN3 with its antibody. Notably, a portion of MATN3 protein is found to form puncta in gastric cancer tissues ECM. MATN3 undergoes phase separation, which is mediated by its low complexity (LC) and coiled‐coil (CC) domains. Moreover, overexpression of MATN3 deleted with either LC or CC in CAFs is unable to promote the invasion of gastric cancer cells, suggesting that LC or CC domain is required for the effect of CAF‐secreted MATN3 in gastric cancer cell invasion. Additionally, orthotopic co‐injection of gastric cancer cells and CAFs expressing MATN3, but not its ΔLC and ΔCC mutants, leads to enhanced gastric cancer cell invasion in mouse models. Collectively, our works suggest that MATN3 is secreted by CAFs and undergoes phase separation, which promotes gastric cancer invasion.
... Research is gradually revealing aspects of the complex control systems of cancer angiogenesis. TNC is highly expressed in the so-called angiomatrix, a matrisomal signature that characterizes the angiogenic switch to enhance angiogenesis [55,56]. It has been shown to promote angiogenesis via Wnt signaling by down-regulating the Wnt inhibitors Dickkopf-1 (DKK1) [49] and ephrin-B2/EPHB4, and also induces anti-angiogenic signaling via the down-regulation of YAP [56]. ...
... TNC is highly expressed in the so-called angiomatrix, a matrisomal signature that characterizes the angiogenic switch to enhance angiogenesis [55,56]. It has been shown to promote angiogenesis via Wnt signaling by down-regulating the Wnt inhibitors Dickkopf-1 (DKK1) [49] and ephrin-B2/EPHB4, and also induces anti-angiogenic signaling via the down-regulation of YAP [56]. Furthermore, TNC promotes tubulogenic activity by inducing FN expression in endothelial cells [57]. ...
Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling.
... Intriguingly, BaP-upregulated genes were enriched in functional categories including vasculature and circulatory system development ( Figure 4D, Supplementary Figure S4C). These vasculature genes included Efnb2, a member of the ephrin family and a pro-angiogenic factor whose overexpression predicts the poor prognosis of solid tumors [43][44][45], and Id1, a helix-loop-helix transcription factor that regulates tumor angiogenesis [46] ( Figure 4E,F). BaP upregulated the expression levels of these pro-angiogenic and pro-tumorigenic factors [47][48][49] in male MRL lungs more than in their female counterparts (Figure 4F). ...
... Immunofluorescence staining also showed that there was an increase in the number of EFNB2-positve cells in the lungs of BaP-treated MRL mice, an effect more Intriguingly, BaP-upregulated genes were enriched in functional categories including vasculature and circulatory system development ( Figure 4D, Supplementary Figure S4C). These vasculature genes included Efnb2, a member of the ephrin family and a pro-angiogenic factor whose overexpression predicts the poor prognosis of solid tumors [43][44][45], and Id1, a helix-loop-helix transcription factor that regulates tumor angiogenesis [46] (Figure 4E,F). BaP upregulated the expression levels of these pro-angiogenic and pro-tumorigenic fac-tors [47][48][49] in male MRL lungs more than in their female counterparts ( Figure 4F). ...
Studies indicate that genetic factors only account for approximately thirty percent of all autoimmune diseases, while the rest of autoimmune pathogenesis is attributed to environmental factors including toxic chemicals. To understand if and how environmental pollutants trigger autoimmunity, we investigated the effect of benzo[a]pyrene (BaP) exposure on the development of autoimmune phenotypes in the lupus-prone MRL strain. The exposure of MRL mice to BaP over the course of 8 weeks before lupus onset resulted in total body weight loss in males, while marginal changes in anti-dsDNA levels occurred. Multi-organ analyses of BaP-treated and control MRL mice suggested that the kidney is a major organ directly affected by the metabolism of benzene-containing compounds, with increased expression of BaP-target genes including Cyp4b1 and Hao2. Intriguingly, spatial transcriptomic data showed that BaP caused a drastic reduction in cell-type diversity in both the kidneys and spleen of MRL mice. Further analysis of the molecular pathways affected suggested a sex-biased effect of BaP treatment, with the upregulated expression of angiogenesis genes in the lungs and an increased deposition of C3 in the kidneys of male mice. While SLE is more common in women, the disease is more severe in male patients, with an increased risk of disease progression to renal failure and lung cancer. Our results reveal sex-biased molecular pathways stimulated by BaP which may help explain the increased likelihood of end organ damage in males with lupus.
... TNC-induced EC rounding has been correlated with an inactivation of the Hippopathway-associated molecule Yes-associated protein (YAP, also known as YAP1), which can act as a sensor of actin stress fibers (Cai et al., 2021). Accordingly, actin stress fibers were abolished upon cell detachment mediated by TNC, thus impairing nuclear shuttling of YAP to drive transcription of target genes (Rupp et al., 2016). Pro-survival YAP targets, including connective tissue growth factor (CTGF; also known as CCN2) and cysteine-rich angiogenic protein 61 (Cyr61; also known as CCN1), were downregulated (Rupp et al., 2016), raising the possibility that repression of pro-angiogenic factors plays a role in TNC-associated vessel leakiness. ...
... Accordingly, actin stress fibers were abolished upon cell detachment mediated by TNC, thus impairing nuclear shuttling of YAP to drive transcription of target genes (Rupp et al., 2016). Pro-survival YAP targets, including connective tissue growth factor (CTGF; also known as CCN2) and cysteine-rich angiogenic protein 61 (Cyr61; also known as CCN1), were downregulated (Rupp et al., 2016), raising the possibility that repression of pro-angiogenic factors plays a role in TNC-associated vessel leakiness. ECs were able to overcome TNC-induced cell death by activating Wnt signaling and subsequent induction of cellular FN to generate an insulating matrix layer (Radwanska et al., 2017). ...
... In GBM, the tumor cells largely contribute to TNC expression (Huang et al., 2010). Gene expression and proteomic analysis of the secretome from cultured human glioblastoma cells with either high or engineered lowered TNC levels revealed that TNC induces several pro-angiogenic factors that promote EC expansion and tubulogenesis in vitro, and angiogenesis and tumor growth in vivo (Rupp et al., 2016). Inhibition of TNC-induced factor ephrin B2 signaling through its receptor EphB4 caused smaller and less vascularized tumors, phenocopying reduced angiogenesis in the TNC knockdown (TNC-KD) tumors (Table 1). ...
The roles of the extracellular matrix molecule tenascin-C (TNC) in health and disease have been extensively reviewed since its discovery over 40 years ago. Here, we will describe recent insights into the roles of TNC in tumorigenesis, angiogenesis, immunity and metastasis. In addition to high levels of expression in tumors, and during chronic inflammation, and bacterial and viral infection, TNC is also expressed in lymphoid organs. This supports potential roles for TNC in immunity control. Advances using murine models with engineered TNC levels were instrumental in the discovery of important functions of TNC as a danger-associated molecular pattern (DAMP) molecule in tissue repair and revealed multiple TNC actions in tumor progression. TNC acts through distinct mechanisms on many different cell types with immune cells coming into focus as important targets of TNC in cancer. We will describe how this knowledge could be exploited for cancer disease management, in particular for immune (checkpoint) therapies.
... Mural cells consisted of smooth muscle cells (SMCs), pericytes, perivascular fibroblasts, and vascular leptomeningeal cells ( Fig. 2b and S2g,h). Upregulation of vascular membrane remodeling (collagen and metalloproteinases), pro-angiogenic genes (e.g., TNC) (Rupp et al., 2016), and proliferative markers were associated with two different subpopulations of SMCs. These phenotypes have not been reported and are consistent with the enhanced microvascular proliferation in GB (Fig. 2b). ...
Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity of the cell states and dynamic changes in GB. Large-scale data integration can help to uncover unexplored tumor pathobiology. Here, we resolved the composition of the tumor milieu and created a cellular map of GB ("GBmap"), a curated resource that harmonizes 26 datasets gathering 240 patients and spanning over 1.1 million cells. We showcase the applications of our resource for reference mapping, transfer learning, and biological discoveries. Our results uncover the sources of pro-angiogenic signaling and the multifaceted role of mesenchymal-like cancer cells. Reconstructing the tumor architecture using spatially resolved transcriptomics unveiled a high level of well-structured neoplastic niches. The GBmap represents a framework that allows the streamlined integration and interpretation of new data and provides a platform for exploratory analysis, hypothesis generation and testing.
