EMBO Molecular Medicine

Journal: EMBO Molecular Medicine

Abbreviation

EMBO Mol Med

Publisher

EMBO Press

ISSN

1757-4676
1757-4684

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Publications 1 - 10 of 39

Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients
Mouliere, Florent; Mair, Richard; Chandrananda, Dineika; et al. (2018)
EMBO Molecular Medicine
Glioma is difficult to detect or characterize using current liquid biopsy approaches. Detection of cell‐free tumor DNA (cftDNA) in cerebrospinal fluid (CSF) has been proposed as an alternative to detection in plasma. We used shallow whole‐genome sequencing (sWGS, at a coverage of < 0.4×) of cell‐free DNA from the CSF of 13 patients with primary glioma to determine somatic copy number alterations and DNA fragmentation patterns. This allowed us to determine the presence of cftDNA in CSF without any prior knowledge of point mutations present in the tumor. We also showed that the fragmentation pattern of cell‐free DNA in CSF is different from that in plasma. This low‐cost screening method provides information on the tumor genome and can be used to target those patients with high levels of cftDNA for further larger‐scale sequencing, such as by whole‐exome and whole‐genome sequencing.
Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages
Antsiferova, Maria; Piwko-Czuchra, Aleksandra; Cangkrama, Michael; et al. (2017)
EMBO Molecular Medicine
Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2‐positive monocytes. Gene expression profiling of macrophages from pre‐tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor‐associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody‐mediated depletion of macrophages, which strongly suppressed activin‐induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.
MicroRNA therapy for infected wounds
Hiebert, Paul; Werner, Sabine (2018)
EMBO Molecular Medicine
A novel approach for identification of functional miRNAs in skin wounds reveals miR‐223 as a key regulator of inflammation during tissue repair. The findings suggest targeting of miR‐233 as an effective strategy to enhance neutrophil activation after bacterial infection and to improve healing of infected wounds.
DGAT inhibition at the post-absorptive phase reduces plasma FA by increasing FA oxidation
Sharma, Anand Kumar; Wolfrum, Christian (2023)
EMBO Molecular Medicine
In this Correspondence, A. Sharma & C. Wolfrum report that DGAT1/2 pharmacological inhibition at post-absorptive phase in mice leads to increased fatty acid oxidation and reduced plasma fatty acid levels, which could open new therapeutic avenues to avoid GI complications observed in clinical trials. image
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Cuttano, Roberto; Rudini, Noemi; Bravi, Luca; et al. (2016)
EMBO Molecular Medicine
Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss‐of‐function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial‐to‐mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP‐dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3‐MEK5‐ERK5‐MEF2 signaling axis that induces a strong increase in Kruppel‐like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1‐null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial‐specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.
The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis
Losa, Marco; Emmenegger, Marc; de Rossi, Pierre; et al. (2024)
EMBO Molecular Medicine
Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard−/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
Src is activated by the nuclear receptor peroxisome proliferator‐activated receptor β/δ in ultraviolet radiation‐induced skin cancer
Montagner, Alexandra; Delgado, Maria B.; Tallichet‐Blanc, Corinne; et al. (2014)
EMBO Molecular Medicine
Although non‐melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator‐activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)‐induced skin cancer in mice. UV‐induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial‐to‐mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ‐null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV‐dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.
Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice
Schäfer, Matthias; Willrodt, Ann-Helen; Kurinna, Svitlana; et al. (2014)
EMBO Molecular Medicine
The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline‐rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin‐induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2‐dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.
Antagonism of interferon signaling by fibroblast growth factors promotes viral replication
Maddaluno, Luigi; Urwyler, Corinne; Rauschendorfer, Theresa; et al. (2020)
EMBO Molecular Medicine
Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross‐talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferon‐stimulated genes (ISG) and proteins in vitro and in vivo. Conversely, FGF7 or FGF10 treatment of keratinocytes suppressed ISG expression under homeostatic conditions and in response to IFN or poly(I:C) treatment. FGF‐mediated ISG suppression was independent of IFN receptors, occurred at the transcriptional level, and required FGF receptor kinase and proteasomal activity. It is not restricted to keratinocytes and functionally relevant, since FGFs promoted the replication of herpes simplex virus I (HSV‐1), lymphocytic choriomeningitis virus, and Zika virus. Most importantly, inhibition of FGFR signaling blocked HSV‐1 replication in cultured human keratinocytes and in mice. These results suggest the use of FGFR kinase inhibitors for the treatment of viral infections.
Regulation of liver regeneration by growth factors and cytokines
Böhm, Friederike; Köhler, Ulrike A.; Speicher, Tobias; et al. (2010)
EMBO Molecular Medicine

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