Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

Francart, Marie-Emilie; Vanwynsberghe, Aline; Lambert, Justine; Bourcy, Morgane; Genna, Anthony; Ancel, Julien; Pérez-Boza, Jennifer; Noël, Agnès; Birembaut, Philippe; Struman, Ingrid; Polette, Myriam; Gilles, Christine

doi:10.1038/s41388-020-1244-1

Cited by 27 publications

(25 citation statements)

References 71 publications

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“…Interestingly, a relationship between TF expression and CSC phenotypes has also been reported [235,236]. The EMT core transcription factors ZEB1 and Snail were delineated to regulate TF expression [234], and recently, vimentin was reported to stabilize TF mRNA [237]. Interestingly, TGF-β, liberated from activated platelets, has been described to trigger EMTs [142], suggesting a regulatory loop between EMT and platelet activation.…”

Section: Activation Of Coagulationmentioning

confidence: 95%

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

Genna

Vanwynsberghe

Villard

et al. 2020

Cancers

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Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine.

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Section: Activation Of Coagulationmentioning

confidence: 95%

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

Genna

Vanwynsberghe

Villard

et al. 2020

Cancers

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“…Tissue factor (TF) is a 47 kDa membrane-associated glycoprotein, which has recently been identified as a link between the hemostatic system and cancer progression [ 135 ]. It is observed that vimentin stabilises TF mRNA, thus promoting coagulant activity and early metastasis [ 136 ].…”

Section: Vimentin Regulating Other Genes During Emtmentioning

confidence: 99%

Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

Usman

Waseem²,

Nguyen

et al. 2021

Cancers

196

112

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Epithelial-mesenchymal transition (EMT) is a reversible plethora of molecular events where epithelial cells gain the phenotype of mesenchymal cells to invade the surrounding tissues. EMT is a physiological event during embryogenesis (type I) but also happens during fibrosis (type II) and cancer metastasis (type III). It is a multifaceted phenomenon governed by the activation of genes associated with cell migration, extracellular matrix degradation, DNA repair, and angiogenesis. The cancer cells employ EMT to acquire the ability to migrate, resist therapeutic agents and escape immunity. One of the key biomarkers of EMT is vimentin, a type III intermediate filament that is normally expressed in mesenchymal cells but is upregulated during cancer metastasis. This review highlights the pivotal role of vimentin in the key events during EMT and explains its role as a downstream as well as an upstream regulator in this highly complex process. This review also highlights the areas that require further research in exploring the role of vimentin in EMT. As a cytoskeletal protein, vimentin filaments support mechanical integrity of the migratory machinery, generation of directional force, focal adhesion modulation and extracellular attachment. As a viscoelastic scaffold, it gives stress-bearing ability and flexible support to the cell and its organelles. However, during EMT it modulates genes for EMT inducers such as Snail, Slug, Twist and ZEB1/2, as well as the key epigenetic factors. In addition, it suppresses cellular differentiation and upregulates their pluripotent potential by inducing genes associated with self-renewability, thus increasing the stemness of cancer stem cells, facilitating the tumour spread and making them more resistant to treatments. Several missense and frameshift mutations reported in vimentin in human cancers may also contribute towards the metastatic spread. Therefore, we propose that vimentin should be a therapeutic target using molecular technologies that will curb cancer growth and spread with reduced mortality and morbidity.

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“…Vimentin is a structural protein found in cells of mesenchymal origin, though it has also been described in activated monocytes, and to a much lesser extent in lymphocytes 42‐45 . It has been associated with the procoagulant effects of metastatic tumor cells through a TF‐dependent mechanism 46 . We therefore examined vimentin expression in and around transplanted islets.…”

Section: Resultsmentioning

confidence: 99%

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation

Song

Fitch

Samy

et al. 2021

Xenotransplantation

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Background Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non‐human primates using a dual‐transplant model to directly compare islet characteristics. Methods α1,3‐Galactosyltransferase gene‐knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro‐thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. Results Xeno‐islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co‐localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. Conclusions These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF‐positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.

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Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial–mesenchymal transitions and facilitates early metastasis

Cited by 27 publications

References 71 publications

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation

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