TY  - JOUR
AB  - Therapeutic options for patients with mesothelioma remain scarce and five-year survival is a meager ten percent. According to data from three large studies, 36% of mesotheliomas harbor neurofibromatosis 2 (NF2) mutations or loss (https://bit.ly/4nGcRXk; accessed on 06.30.2025), yet no targeted therapy exists for this molecular subtype of the disease. In the current issue of EMBO Molecular Medicine, Xu et al, demonstrate that NF2-deficiency of mesothelioma cells releases an NF2-mediated Hippo-pathway restraint, activates the Yes-associated protein (YAP)–carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD)/dihydroorotate dehydrogenase (DHODH) axis, and drives addiction to high-flux de novo pyrimidine biosynthesis (Xu et al, 2025). Moreover, the authors elegantly show that DHODH inhibitors elicit robust antitumor activity against NF2-altered mesothelioma and exhibit strong synergy with cisplatin, opening a new translational avenue for this tumor subtype.
AU  - Jia, J.
AU  - Stathopoulos, G.T.
C1  - 75239
C2  - 57868
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 2165-2167
TI  - Pyrimidine addiction: An Achilles' heel of NF2-altered mesothelioma.
JO  - EMBO Mol. Med.
VL  - 17
IS  - 9
PB  - Springernature
PY  - 2025
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc- . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.
AU  - Alborzinia, H.*
AU  - Chen, Z.*
AU  - Yildiz, U.*
AU  - Freitas, F.P.*
AU  - Vogel, F.C.E.*
AU  - Varga, J.P.*
AU  - Batani, J.*
AU  - Bartenhagen, C.*
AU  - Schmitz, W.*
AU  - Büchel, G.*
AU  - Michalke, B.
AU  - Zheng, J.
AU  - Meierjohann, S.*
AU  - Girardi, E.*
AU  - Espinet, E.*
AU  - Flórez, A.F.*
AU  - Dos Santos, A.F.*
AU  - Aroua, N.*
AU  - Cheytan, T.*
AU  - Haenlin, J.*
AU  - Schlicker, L.*
AU  - Xavier da Silva, T.N.*
AU  - Przybylla, A.*
AU  - Zeisberger, P.*
AU  - Superti-Furga, G.*
AU  - Eilers, M.*
AU  - Conrad, M.
AU  - Fabiano, M.*
AU  - Schweizer, U.*
AU  - Fischer, M.*
AU  - Schulze, A.*
AU  - Trumpp, A.*
AU  - Friedmann Angeli, J.P.*
C1  - 68116
C2  - 54594
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.
JO  - EMBO Mol. Med.
VL  - 15
IS  - 8
PB  - Wiley
PY  - 2023
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castration-resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten(i)pe-/- mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castration-resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia-inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten(i)pe-/- mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten-deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.
AU  - Terzic, J.*
AU  - Abu El Maaty, M.A.
AU  - Lutzing, R.*
AU  - Vincent, A.*
AU  - El Bizri, R.*
AU  - Jung, M.*
AU  - Keime, C.*
AU  - Metzger, D.*
C1  - 67690
C2  - 53997
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Hypoxia-inducible factor 1A inhibition overcomes castration resistance of prostate tumors.
JO  - EMBO Mol. Med.
VL  - 15
IS  - 6
PB  - Wiley
PY  - 2023
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM-sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy-induced cell death via caspases and PARP, but independent from cIAP-1/2, RIPK1, TNFα or NF-κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA-30 flanked shRNA expression in cell lines and patient-derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown-sensitized r/r ALL cells towards chemotherapy-induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL.
AU  - Carlet, M.
AU  - Schmelz, K.*
AU  - Vergalli, J.
AU  - Herold, T.
AU  - Senft, D.
AU  - Jurinovic, V.
AU  - Hoffmann, T.*
AU  - Proba, J.*
AU  - Weichert, N.*
AU  - Junghanß, C.*
AU  - Roth, M.*
AU  - Eschenburg, G.*
AU  - Barz, M.*
AU  - Henze, G.*
AU  - Eckert, C.*
AU  - Eggert, A.*
AU  - Zuber, J.*
AU  - Hundsdoerfer, P.*
AU  - Jeremias, I.
C1  - 66833
C2  - 53307
TI  - X-linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL.
JO  - EMBO Mol. Med.
PY  - 2022
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single-cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.
AU  - Giehrl-Schwab, J.
AU  - Giesert, F.
AU  - Rauser, B.
AU  - Lao, C.L.
AU  - Hembach, S.
AU  - Lefort, S.
AU  - Ibarra Del Rio, I.A.
AU  - Koupourtidou, C.
AU  - Luecken, M.
AU  - Truong, D.-J.J.
AU  - Fischer-Sternjak, J.
AU  - Masserdotti, G.
AU  - Prakash, N.*
AU  - Ninkovic, J.
AU  - Hölter, S.M.
AU  - Vogt Weisenhorn, D.M.
AU  - Theis, F.J.
AU  - Götz, M.
AU  - Wurst, W.
C1  - 64746
C2  - 51956
TI  - Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons.
JO  - EMBO Mol. Med.
PY  - 2022
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas-mediated gene repair or gene therapy in vitro. AAV-based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.
AU  - Grotz, S.*
AU  - Schäfer, J.*
AU  - Wunderlich, K.A.*
AU  - Ellederova, Z.*
AU  - Auch, H.*
AU  - Bähr, A.*
AU  - Runa-Vochozkova, P.*
AU  - Fadl, J.*
AU  - Arnold, V.*
AU  - Ardan, T.*
AU  - Veith, M.*
AU  - Santamaria, G.*
AU  - Dhom, G.*
AU  - Hitzl, W.*
AU  - Kessler, B.*
AU  - Eckardt, C.*
AU  - Klein, J.*
AU  - Brymova, A.*
AU  - Linnert, J.*
AU  - Kurome, M.*
AU  - Zakharchenko, V.*
AU  - Fischer, A.*
AU  - Blutke, A.
AU  - Döring, A.*
AU  - Suchankova, S.*
AU  - Popelar, J.*
AU  - Rodríguez-Bocanegra, E.*
AU  - Dlugaiczyk, J.*
AU  - Straka, H.*
AU  - May-Simera, H.*
AU  - Wang, W.*
AU  - Laugwitz, K.L.*
AU  - Vandenberghe, L.H.*
AU  - Wolf, E.*
AU  - Nagel-Wolfrum, K.*
AU  - Peters, T.*
AU  - Motlik, J.*
AU  - Fischer, M.D.*
AU  - Wolfrum, U.*
AU  - Klymiuk, N.*
C1  - 64508
C2  - 51958
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2022
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF-PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on the microenvironmental cues that are essential for tumor progression.
AU  - Minaskan Karabid, N.
AU  - Wiedemann, T.
AU  - Gulde, S.
AU  - Mohr, H.
AU  - Segaran Renu, C.
AU  - Geppert, J.
AU  - Rohm, M.
AU  - Vitale, G.*
AU  - Gaudenzi, G.*
AU  - Dicitore, A.*
AU  - Ankerst, D.P.*
AU  - Chen, Y.*
AU  - Braren, R.*
AU  - Kaissis, G.*
AU  - Schilling, F.*
AU  - Schillmaier, M.*
AU  - Eisenhofer, G.*
AU  - Herzig, S.
AU  - Roncaroli, F.*
AU  - Honegger, J.B.*
AU  - Pellegata, N.S.
C1  - 64582
C2  - 51957
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Angpt2/Tie2 autostimulatory loop controls tumorigenesis.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2022
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
AU  - Hartleben, G.
AU  - Schorpp, K.K.
AU  - Kwon, Y.
AU  - Betz, B.
AU  - Tsokanos, F.-F.
AU  - Dantes, Z.*
AU  - Schäfer, A.*
AU  - Rothenaigner, I.
AU  - Monroy Kuhn, J.M.
AU  - Morigny, P.
AU  - Mehr, L.
AU  - Lin, S.
AU  - Seitz, S.
AU  - Tokarz, J.
AU  - Artati, A.
AU  - Adamski, J.
AU  - Plettenburg, O.
AU  - Lutter, D.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Reichert, M.*
AU  - Hadian, K.
AU  - Zeigerer, A.
AU  - Herzig, S.
AU  - Berriel Diaz, M.
C1  - 61448
C2  - 49908
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4+ , CD8+ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.
AU  - Hirschberger, S.*
AU  - Strauß, G.*
AU  - Effinger, D.*
AU  - Marstaller, X.*
AU  - Ferstl, A.*
AU  - Müller, M.B.*
AU  - Wu, T.*
AU  - Hübner, M.*
AU  - Rahmel, T.*
AU  - Mascolo, H.*
AU  - Exner, N.*
AU  - Hess J.
AU  - Kreth, F.W.*
AU  - Unger, K.
AU  - Kreth, S.*
C1  - 62317
C2  - 50769
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The increasing worldwide prevalence of obesity, fatty liver diseases and the emerging understanding of the important roles lipids play in various other diseases is generating significant interest in lipid research. Lipid visualization in particular can play a critical role in understanding functional relations in lipid metabolism. We investigated the potential of multispectral optoacoustic tomography (MSOT) as a novel modality to non-invasively visualize lipids in laboratory mice around the 930nm spectral range. Using an obesity-induced non-alcoholic fatty liver disease (NAFLD) mouse model, we examined whether MSOT could detect and differentiate different grades of hepatic steatosis and monitor the accumulation of lipids in the liver quantitatively over time, without the use of contrast agents, i.e. in label-free mode. Moreover, we demonstrate the efficacy of using the real-time clearance kinetics of indocyanine green (ICG) in the liver, monitored by MSOT, as a biomarker to evaluate the organ’s function and assess the severity of NAFLD. This study establishes MSOT as an efficient imaging tool for lipid visualization in preclinical studies, particularly for the assessment of NAFLD.
AU  - Huang, S.
AU  - Blutke, A.
AU  - Feuchtinger, A.
AU  - Klemm, U.*
AU  - Zachariah Tom, R.
AU  - Hofmann, S.M.
AU  - Stiel, A.C.*
AU  - Ntziachristos, V.
C1  - 62823
C2  - 51080
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Functional multispectral optoacoustic tomography imaging of hepatic steatosis development in mice.
JO  - EMBO Mol. Med.
VL  - 13
IS  - 9
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.
AU  - Marazioti, A.
AU  - Krontira, A.C.*
AU  - Behrend, S.J.
AU  - Giotopoulou, G.A.
AU  - Ntaliarda, G.*
AU  - Blanquart, C.*
AU  - Bayram, H.*
AU  - Iliopoulou, M.*
AU  - Vreka, M.
AU  - Trassl, L.
AU  - Pepe, M.
AU  - Hackl, C.M.
AU  - Klotz, L.V.
AU  - Weiss, S.A.
AU  - Koch, I.*
AU  - Lindner, M.*
AU  - Hatz, R.A.*
AU  - Behr, J.
AU  - Wagner, D.E.
AU  - Papadaki, H.*
AU  - Antimisiaris, S.G.*
AU  - Jean, D.*
AU  - Deshayes, S.*
AU  - Grégoire, M.*
AU  - Kayalar,*
AU  - Mortazavi, D.*
AU  - Dilege,*
AU  - Tanju, S.*
AU  - Erus, S.*
AU  - Yavuz, Ö.*
AU  - Bulutay, P.*
AU  - Fırat, P.*
AU  - Psallidas, I.*
AU  - Spella, M.*
AU  - Giopanou, I.*
AU  - Lilis, I.*
AU  - Lamort, A.-S.
AU  - Stathopoulos, G.T.
C1  - 63773
C2  - 51609
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - KRAS signaling in malignant pleural mesothelioma.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single-cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single-cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type-2 epithelial cell health status in lavage fluid and plasma. Using cross-modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.
AU  - Mayr, C.
AU  - Simon, L.
AU  - Leuschner, G.
AU  - Ansari, M.
AU  - Schniering, J.
AU  - Geyer, P.E.*
AU  - Angelidis, I.
AU  - Strunz, M.
AU  - Singh, P.
AU  - Kneidinger, N.
AU  - Reichenberger, F.
AU  - Silbernagel, E.*
AU  - Böhm, S.*
AU  - Adler, H.
AU  - Lindner, M.
AU  - Maurer, B.*
AU  - Hilgendorff, A.
AU  - Prasse, A.*
AU  - Behr, J.
AU  - Mann, M.*
AU  - Eickelberg, O.*
AU  - Theis, F.J.
AU  - Schiller, H. B.
C1  - 61462
C2  - 50271
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers.
JO  - EMBO Mol. Med.
VL  - 13
IS  - 4
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Aberrant production of ceramides, the precursors of complex sphingolipids, is a hallmark of obesity and strongly linked to metabolic dysfunction (Meikle and Summers 2017). Ceramides are formed by recycling or de novo synthesis from sphingosine and a fatty acid side chain moiety. The side chain length determines lipotoxicity of ceramides, as those composed of C16:0 or C18:0 side chains are toxic whereas those with C24:0 or C24:1 are not (Meikle and Summers 2017). Counteracting the deleterious effects of high-fat diets (HFDs) rich in saturated fat either by inhibiting synthesis or by promoting degradation of ceramides mitigates insulin resistance and ectopic lipid accumulation (Meikle and Summers 2017). However, drugs that safely and selectively target ceramide metabolism have failed to translate into metabolic benefit in human trials so far.
AU  - Muley, C.*
AU  - Bartelt, A.
C1  - 62647
C2  - 50986
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Fuse your mitochondria, lose appetite: An anorexic, anti-obesity sphingolipid.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.
AU  - Vidali, S.
AU  - Gerlini, R.
AU  - Thompson, K.*
AU  - Urquhart, J.E.*
AU  - Meisterknecht, J.*
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Becker, L.
AU  - Breen, C.*
AU  - Calzada-Wack, J.
AU  - Chhabra, N.F.
AU  - Cho, Y.-L.
AU  - da Silva Buttkus, P.
AU  - Feichtinger, R.G.*
AU  - Gampe, K.
AU  - Garrett, L.
AU  - Hoefig, K.P.
AU  - Hölter, S.M.
AU  - Jameson, E.*
AU  - Klein-Rodewald, T.
AU  - Leuchtenberger, S.
AU  - Marschall, S.
AU  - Mayer-Kuckuk, P.
AU  - Miller, G.
AU  - Oestereicher, M.A.
AU  - Pfannes, K.
AU  - Rathkolb, B.
AU  - Rozman, J.
AU  - Sanders, C.*
AU  - Spielmann, N.
AU  - Stoeger, C.
AU  - Szibor, M.*
AU  - Treise, I.
AU  - Walter, J.H.*
AU  - Wurst, W.
AU  - Mayr, J.A.*
AU  - Fuchs, H.
AU  - Gärtner, U.*
AU  - Wittig, I.*
AU  - Taylor, R.W.*
AU  - Newman, W.G.*
AU  - Prokisch, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
C1  - 63495
C2  - 51335
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Characterising a homozygous two-exon deletion in UQCRH: Comparing human and mouse phenotypes.
JO  - EMBO Mol. Med.
PB  - Wiley
PY  - 2021
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Progressive myoclonus epilepsy (PME) of Unverricht–Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors’ proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients’ hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.
AU  - Di Matteo, F.*
AU  - Pipicelli, F.*
AU  - Kyrousi, C.*
AU  - Tovecci, I.*
AU  - Penna, E.*
AU  - Crispino, M.*
AU  - Chambery, A.*
AU  - Russo, R.*
AU  - Ayo-Martin, A.C.*
AU  - Giordano, M.*
AU  - Hoffmann, A.*
AU  - Ciusani, E.*
AU  - Canafoglia, L.*
AU  - Götz, M.
AU  - Di Giaimo, R.*
AU  - Cappello, S.*
C1  - 59057
C2  - 48549
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.
JO  - EMBO Mol. Med.
VL  - 12
IS  - 6
PB  - Wiley
PY  - 2020
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ-specific manner. Insulin flux across the endothelium to muscle cells is a rate-limiting process influencing insulin-mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non-obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC-specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high-fat diet-induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes.
AU  - Hasan, S.S.*
AU  - Jabs, M.*
AU  - Taylor, J.*
AU  - Wiedmann, L.*
AU  - Leibing, T.*
AU  - Nordström, V.*
AU  - Federico, G.*
AU  - Roma, L.P.*
AU  - Carlein, C.*
AU  - Wolff, G.
AU  - Ekim-Üstünel, B.
AU  - Brune, M.*
AU  - Moll, I.*
AU  - Tetzlaff, F.*
AU  - Gröne, H.J.*
AU  - Fleming, T.*
AU  - Géraud, C.*
AU  - Herzig, S.
AU  - Nawroth, P.P.
AU  - Fischer, A.*
C1  - 58619
C2  - 48363
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Endothelial Notch signaling controls insulin transport in muscle.
JO  - EMBO Mol. Med.
VL  - 12
IS  - 4
PB  - Wiley
PY  - 2020
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., alpha-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for alpha-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid beta-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.
AU  - Schlepckow, K.*
AU  - Monroe, K.M.*
AU  - Kleinberger, G.*
AU  - Cantuti-Castelvetri, L.*
AU  - Parhizkar, S.*
AU  - Xia, D.*
AU  - Willem, M.*
AU  - Werner, G.*
AU  - Pettkus, N.*
AU  - Brunner, B.*
AU  - Sülzen, A.*
AU  - Nuscher, B.*
AU  - Hampel, H.*
AU  - Xiang, X.*
AU  - Feederle, R.
AU  - Tahirovic, S.*
AU  - Park, J.I.*
AU  - Prorok, R.*
AU  - Mahon, C.*
AU  - Liang, C.C.*
AU  - Shi, J.*
AU  - Kim, D.J.*
AU  - Sabelström, H.*
AU  - Huang, F.*
AU  - Di Paolo, G.*
AU  - Simons, M.*
AU  - Lewcock, J.W.*
AU  - Haass, C.*
C1  - 58547
C2  - 48452
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.
JO  - EMBO Mol. Med.
VL  - 12
IS  - 4
PB  - Wiley
PY  - 2020
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)(149)-CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)(149)-CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)(10) conjugates and pre-aggregated carrier-free (GA)(15). Only ovalbumin-(GA)(10) immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)(10) immunization largely rescued the motor function in (GA)(149)-CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)(10)-immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.
AU  - Zhou, Q.*
AU  - Mareljic, N.*
AU  - Michaelsen, M.*
AU  - Parhizkar, S.*
AU  - Heindl, S.*
AU  - Nuscher, B.*
AU  - Farny, D.*
AU  - Czuppa, M.*
AU  - Schludi, C.*
AU  - Graf, A.*
AU  - Krebs, S.*
AU  - Blum, H.*
AU  - Feederle, R.
AU  - Roth, S.*
AU  - Haass, C.*
AU  - Arzberger, T.*
AU  - Liesz, A.*
AU  - Edbauer, D.*
C1  - 57693
C2  - 47888
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model.
JO  - EMBO Mol. Med.
VL  - 12
IS  - 2
PB  - Wiley
PY  - 2020
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn−/− mice and compared their transcriptomes to those of Trem2−/− mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn−/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.
AU  - Götzl, J.K.*
AU  - Brendel, M.*
AU  - Werner, G.*
AU  - Parhizkar, S.*
AU  - Sebastian Monasor, L.*
AU  - Kleinberger, G.*
AU  - Colombo, A.V.*
AU  - Deussing, M.*
AU  - Wagner, M.
AU  - Winkelmann, J.
AU  - Diehl-Schmid, J.*
AU  - Levin, J.*
AU  - Fellerer, K.*
AU  - Reifschneider, A.*
AU  - Bultmann, S.*
AU  - Bartenstein, P.*
AU  - Rominger, A.*
AU  - Tahirovic, S.*
AU  - Smith, S.T.*
AU  - Madore, C.*
AU  - Butovsky, O.*
AU  - Capell, A.*
AU  - Haass, C.*
C1  - 56171
C2  - 46863
SP  - e9711
TI  - Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism.
JO  - EMBO Mol. Med.
VL  - 11
IS  - 5
PY  - 2019
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.
AU  - Bayindir-Buchhalter, I.*
AU  - Wolff, G.*
AU  - Lerch, S.*
AU  - Sijmonsma, T.*
AU  - Schuster, M.*
AU  - Gronych, J.*
AU  - Billeter, A.T.*
AU  - Babaei, R.*
AU  - Krunic, D.*
AU  - Ketscher, L.*
AU  - Spielmann, N.
AU  - Hrabě de Angelis, M.
AU  - Ruas, J.L.*
AU  - Müller-Stich, B.P.*
AU  - Heikenwalder, M.*
AU  - Lichter, P.*
AU  - Herzig, S.
AU  - Vegiopoulos, A.*
C1  - 53876
C2  - 45031
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 7
PB  - Wiley
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9(R239X) mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of beta-resorcylic acid (beta-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. beta-RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone-9 (DMQ(9)) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down-regulation of astrocytes-related neuroinflammatory genes. Because the therapeutic outcomes of beta-RA administration were superior to those after CoQ(10) supplementation, its use in the clinic should be considered in CoQ deficiencies.
AU  - Hidalgo-Gutiérrez, A.*
AU  - Barriocanal-Casado, E.*
AU  - Bakkali, M.*
AU  - Díaz-Casado, M.E.*
AU  - Sánchez-Maldonado, L.*
AU  - Romero, M.*
AU  - Sayed, R.K.*
AU  - Prehn, C.
AU  - Escames, G.*
AU  - Duarte, J.*
AU  - Acuña-Castroviejo, D.*
AU  - López, L.C.*
C1  - 54857
C2  - 45928
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - beta-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9(R239X) mice.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 12
PB  - Wiley
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β‐resorcylic acid (β‐RA), a structural analog of the CoQ precursor 4‐hydroxybenzoic acid and the anti‐inflammatory salicylic acid. β‐RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone‐9 (DMQ9) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down‐regulation of astrocytes‐related neuroinflammatory genes. Because the therapeutic outcomes of β‐RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies.
AU  - Hidalgo-Gutiérrez, A.*
AU  - Barriocanal-Casado, E.*
AU  - Bakkali, M.*
AU  - Díaz-Casado, M.E.*
AU  - Sánchez-Maldonado, L.*
AU  - Romero, M.*
AU  - Sayed, R.K.*
AU  - Prehn, C.
AU  - Escames, G.*
AU  - Duarte, J.*
AU  - Acuña-Castroviejo, D.*
AU  - López, L.C.*
C1  - 54851
C2  - 0
TI  - β‐RA reduced DMQ/CoQ ration and rescues the encephalopathic phenotype in Coq9R239X mice.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 11
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus-associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD. In both COPD patients and cigarette smoke (CS)-exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS-induced B-cell migration and iBALT formation. Mice deficient in CH25H or the oxysterol receptor EBI2 exhibited decreased iBALT and subsequent CS-induced emphysema. Further, inhibition of the oxysterol pathway using clotrimazole resolved iBALT formation and attenuated CS-induced emphysema in vivo therapeutically. Collectively, our studies are the first to mechanistically interrogate oxysterol-dependent iBALT formation in the pathogenesis of COPD, and identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs.
AU  - Jia, J.
AU  - Conlon, T.M.
AU  - Sarker, R.S.
AU  - Taşdemir, D.*
AU  - Smirnova, N.F.
AU  - Srivastava, B.
AU  - Verleden, S.E.*
AU  - Güneş, G.
AU  - Wu, X.
AU  - Prehn, C.*
AU  - Gao, J.
AU  - Heinzelmann, K.
AU  - Lintelmann, J.
AU  - Irmler, M.
AU  - Pfeiffer, S.
AU  - Schloter, M.
AU  - Zimmermann, R.
AU  - Hrabě de Angelis, M.
AU  - Beckers, J.
AU  - Adamski, J.
AU  - Bayram, H.*
AU  - Eickelberg, O.
AU  - Yildirim, A.Ö.
C1  - 53435
C2  - 44556
TI  - Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 4
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.
AU  - Otten, C.*
AU  - Knox, J.P.*
AU  - Boulday, G.*
AU  - Eymery, M.*
AU  - Haniszewski, M.*
AU  - Neuenschwander, M.*
AU  - Radetzki, S.*
AU  - Vogt, I.
AU  - Hähn, K.*
AU  - De Luca, C.*
AU  - Cardoso, C.C.*
AU  - Hamad, S.
AU  - Igual Gil, C.*
AU  - Roy, P.P.*
AU  - Albiges-Rizo, C.*
AU  - Faurobert, E.*
AU  - von Kries, J.P.*
AU  - Campillos, M.
AU  - Tournier-Lasserve, E.*
AU  - Derry, W.B.*
AU  - Abdelilah-Seyfried, S.*
C1  - 54312
C2  - 45479
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 9
PB  - Wiley
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)-deficient Bcs1l(p.S78G) knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.
AU  - Rajendran, J.*
AU  - Purhonen, J.*
AU  - Tegelberg, S.*
AU  - Smolander, O.P.*
AU  - Mörgelin, M.*
AU  - Rozman, J.
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Auvinen, P.*
AU  - Mervaala, E.*
AU  - Jacobs, H.T.*
AU  - Szibor, M.*
AU  - Fellman, V.*
AU  - Kallijärvi, J.*
C1  - 54935
C2  - 45930
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 12
PB  - Wiley
PY  - 2018
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Published under the terms of the CC BY 4.0 license Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-β1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3 −/− ) or fibroblast-specific (Foxo3 f.b −/− ) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin-induced lung fibrosis in vivo. These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.
AU  - Al-Tamari, H.M.*
AU  - Dabral, S.*
AU  - Schmall, A.*
AU  - Sarvari, P.*
AU  - Ruppert, C.*
AU  - Paik, J.*
AU  - DePinho, R.A.*
AU  - Grimminger, F.*
AU  - Eickelberg, O.
AU  - Guenther, A.*
AU  - Seeger, W.*
AU  - Savai, R.*
AU  - Pullamsetti, S.S.*
C1  - 52508
C2  - 44025
SP  - 276-293
TI  - FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis.
JO  - EMBO Mol. Med.
VL  - 10
IS  - 2
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2-deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin-8-related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model where NRAS-mutant, chemokine-expressing circulating tumor cells target the CXCR1-expressing lung vasculature and recruit CXCR2-expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS-driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL-8-related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
AU  - Giannou, A.D.*
AU  - Marazioti, A.*
AU  - Kanellakis, N.I.*
AU  - Giopanou, I.*
AU  - Lilis, I.*
AU  - Zazara, D.E.*
AU  - Ntaliarda, G.*
AU  - Kati, D.*
AU  - Armenis, V.*
AU  - Giotopoulou, G.A.*
AU  - Krontira, A.C.*
AU  - Lianou, M.*
AU  - Agalioti, T.*
AU  - Vreka, M.
AU  - Papageorgopoulou, M.*
AU  - Fouzas, S.*
AU  - Kardamakis, D.*
AU  - Psallidas, I.*
AU  - Spella, M.*
AU  - Stathopoulos, G.T.
C1  - 50800
C2  - 42889
CY  - Hoboken
SP  - 672-686
TI  - NRAS destines tumor cells to the lungs.
JO  - EMBO Mol. Med.
VL  - 9
IS  - 5
PB  - Wiley
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly-GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly-GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly-GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly-GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target.
AU  - Lehmer, C.*
AU  - Oeckl, P.*
AU  - Weishaupt, J.H.*
AU  - Volk, A.E.*
AU  - Diehl-Schmid, J.*
AU  - Schroeter, M.L.*
AU  - Lauer, M.*
AU  - Kornhuber, J.*
AU  - Levin, J.*
AU  - Fassbender, K.*
AU  - Landwehrmeyer, B.*
AU  - Schludi, M.H.*
AU  - Arzberger, T.*
AU  - Kremmer, E.
AU  - Flatley, A.
AU  - Feederle, R.
AU  - Steinacker, P.*
AU  - Weydt, P.*
AU  - Ludolph, A.C.*
AU  - Edbauer, D.*
AU  - Otto, M.*
C1  - 50929
C2  - 42980
CY  - Hoboken
SP  - 859-868
TI  - Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD.
JO  - EMBO Mol. Med.
VL  - 9
IS  - 7
PB  - Wiley
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2 In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A. TGF-β contributes to the PDGF-Rα-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O2 Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O2.
AU  - Oak, P.
AU  - Pritzke, T.
AU  - Thiel, I.
AU  - Koschlig, M.
AU  - Mous, D.S.*
AU  - Windhorst, A.*
AU  - Jain, N.*
AU  - Eickelberg, O.
AU  - Foerster, K.*
AU  - Schulze, A.*
AU  - Goepel, W.*
AU  - Reicherzer, T.*
AU  - Ehrhardt, H.*
AU  - Rottier, R.J.*
AU  - Ahnert, P.*
AU  - Gortner, L.*
AU  - Desai, T.J.*
AU  - Hilgendorff, A.
C1  - 51914
C2  - 43573
CY  - Hoboken
SP  - 1504-1520
TI  - Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease.
JO  - EMBO Mol. Med.
VL  - 9
IS  - 11
PB  - Wiley
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C-terminal to histidine 157, a position where an AD-associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig-like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full-length TREM2 and lowers TREM2-dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2.
AU  - Schlepckow, K.*
AU  - Kleinberger, G.*
AU  - Fukumori, A.*
AU  - Feederle, R.
AU  - Lichtenthaler, S.F.*
AU  - Steiner, H.*
AU  - Haass, C.*
C1  - 52109
C2  - 43758
CY  - Hoboken
SP  - 1356-1365
TI  - An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.
JO  - EMBO Mol. Med.
VL  - 9
IS  - 10
PB  - Wiley
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.
AU  - Zhou, Q.*
AU  - Lehmer, C.*
AU  - Michaelsen, M.*
AU  - Mori, K.*
AU  - Alterauge, D.*
AU  - Baumjohann, D.*
AU  - Schludi, M.H.*
AU  - Greiling, J.*
AU  - Farny, D.*
AU  - Flatley, A.
AU  - Feederle, R.
AU  - May, S.*
AU  - Schreiber, F.*
AU  - Arzberger, T.*
AU  - Kuhm, C.*
AU  - Klopstock, T.*
AU  - Hermann, A.*
AU  - Haass, C.*
AU  - Edbauer, D.*
C1  - 50825
C2  - 42911
CY  - Hoboken
SP  - 687-702
TI  - Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins.
JO  - EMBO Mol. Med.
VL  - 9
IS  - 5
PB  - Wiley
PY  - 2017
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function.
AU  - Fuhrmeister, J.*
AU  - Zota, A.
AU  - Sijmonsma, T.P.*
AU  - Seibert, O.*
AU  - Cingır, S.*
AU  - Schmidt, K.*
AU  - Vallon, N.*
AU  - de Guia, R.M.*
AU  - Niopek, K.
AU  - Berriel Diaz, M.
AU  - Maida, A.
AU  - Blüher, M.*
AU  - Okun, J.G.*
AU  - Herzig, S.
AU  - Rose, A.J.*
C1  - 48526
C2  - 41140
SP  - 654-669
TI  - Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.
JO  - EMBO Mol. Med.
VL  - 8
IS  - 6
PY  - 2016
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal amyloid precursor protein fragment by γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD. We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43-containing plaques in brains of patients with this mutation. The aberrant generation of Aβ43 by this particular mutant provides a direct objection against the presenilin hypothesis.
AU  - Kretner, B.*
AU  - Trambauer, J.*
AU  - Fukumori, A.*
AU  - Mielke, J.*
AU  - Kuhn, P.H.*
AU  - Kremmer, E.
AU  - Giese, A.*
AU  - Lichtenthaler, S.F.*
AU  - Haass, C.*
AU  - Arzberger, T.*
AU  - Steiner, H.*
C1  - 48153
C2  - 39949
SP  - 458-465
TI  - Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.
JO  - EMBO Mol. Med.
VL  - 8
IS  - 5
PY  - 2016
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Hepatitis B virus (HBV) is a promising target for therapies based on RNA interference (RNAi) since it replicates via RNA transcripts that are vulnerable to RNAi silencing. Clinical translation of RNAi technology, however, requires improvements in potency, specificity and safety. To this end, we systematically compared different strategies to express anti-HBV short hairpin RNA (shRNA) in a pre-clinical immunocompetent hepatitis B mouse model. Using recombinant Adeno-associated virus (AAV) 8 vectors for delivery, we either (i) embedded the shRNA in an artificial mi(cro)RNA under a liver-specific promoter; (ii) co-expressed Argonaute-2, a rate-limiting cellular factor whose saturation with excess RNAi triggers can be toxic; or (iii) co-delivered a decoy ("TuD") directed against the shRNA sense strand to curb off-target gene regulation. Remarkably, all three strategies minimised adverse side effects as compared to a conventional shRNA vector that caused weight loss, liver damage and dysregulation of > 100 hepatic genes. Importantly, the novel AAV8 vector co-expressing anti-HBV shRNA and TuD outperformed all other strategies regarding efficiency and persistence of HBV knock-down, thus showing substantial promise for clinical translation.
AU  - Michler, T.
AU  - Große, S.*
AU  - Mockenhaupt, S.*
AU  - Röder, N.
AU  - Stückler, F.
AU  - Knapp, B.
AU  - Ko, C.
AU  - Heikenwälder, M.
AU  - Protzer, U.
AU  - Grimm, D.*
C1  - 49194
C2  - 41696
CY  - Hoboken
SP  - 1082-1098
TI  - Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA.
JO  - EMBO Mol. Med.
VL  - 8
IS  - 9
PB  - Wiley-blackwell
PY  - 2016
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody-mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti-Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose-dependent manner in the presence or absence of TREM2. However, TREM2-deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody-bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.
AU  - Xiang, X.*
AU  - Werner, G.*
AU  - Bohrmann, B.*
AU  - Liesz, A.*
AU  - Mazaheri, F.*
AU  - Capell, A.*
AU  - Feederle, R.
AU  - Knuesel, I.*
AU  - Kleinberger, G.*
AU  - Haass, C.*
C1  - 49061
C2  - 41600
CY  - Hoboken
SP  - 992-1004
TI  - TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.
JO  - EMBO Mol. Med.
VL  - 8
IS  - 9
PB  - Wiley-blackwell
PY  - 2016
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.
AU  - Clemmensen, C.
AU  - Finan, B.
AU  - Fischer, K.
AU  - Tom, R.Z.
AU  - Legutko, B.
AU  - Sehrer, L.
AU  - Heine, D.
AU  - Grassl, N.
AU  - Meyer, C.W.
AU  - Henderson, B.*
AU  - Hofmann, S.M.
AU  - Tschöp, M.H.
AU  - van der Ploeg, L.H.T.*
AU  - Müller, T.D.
C1  - 43232
C2  - 36353
SP  - 288-298
TI  - Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice.
JO  - EMBO Mol. Med.
VL  - 7
IS  - 3
PY  - 2015
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.
AU  - Stoy, C.*
AU  - Sundaram, A.*
AU  - Rios Garcia, M.*
AU  - Wang, X.*
AU  - Seibert, O.*
AU  - Zota, A.
AU  - Wendler, S.*
AU  - Männle, D.*
AU  - Hinz, U.*
AU  - Sticht, C.*
AU  - Muciek, M.*
AU  - Gretz, N.*
AU  - Rose, A.J.*
AU  - Greiner, V.*
AU  - Hofmann, T.G.*
AU  - Bauer, A.*
AU  - Hoheisel, J.*
AU  - Berriel Diaz, M.
AU  - Gaida, M.M.*
AU  - Werner, J.*
AU  - Schafmeier, T.
AU  - Strobel, O.*
AU  - Herzig, S.
C1  - 45192
C2  - 37251
SP  - 1048-1062
TI  - Transcriptional co-factor Transducin Beta-Like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy.
JO  - EMBO Mol. Med.
VL  - 7
IS  - 8
PY  - 2015
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non-alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell deathso far characterized as hepatocyte apoptosisrepresents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3-dependent necroptosis in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.
AU  - Gautheron, J.*
AU  - Vucur, M.*
AU  - Reisinger, F.
AU  - Cardenas, D.V.*
AU  - Roderburg, C.*
AU  - Koppe, C.*
AU  - Kreggenwinkel, K.*
AU  - Schneider, A.T.*
AU  - Bartneck, M.*
AU  - Neumann, U.P.*
AU  - Canbay, A.*
AU  - Reeves, H.L.*
AU  - Luedde, M.*
AU  - Tacke, F.*
AU  - Trautwein, C.*
AU  - Heikenwälder, M.
AU  - Luedde, T.*
C1  - 32177
C2  - 34706
CY  - Hoboken
SP  - 1062-1074
TI  - A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis.
JO  - EMBO Mol. Med.
VL  - 6
IS  - 8
PB  - Wiley-Blackwell
PY  - 2014
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis.
AU  - Hohenauer, Z.*
AU  - Berking, C.*
AU  - Schmidt, A.*
AU  - Haferkamp, S.*
AU  - Senft, D.*
AU  - Kammerbauer, C.*
AU  - Fraschka, S.*
AU  - Graf, S.A.*
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Flaig, M.*
AU  - Aigner, A.*
AU  - Höbel, S.*
AU  - Hoffmann, F.*
AU  - Hermeking, H.*
AU  - Rothenfusser, S.*
AU  - Endres, S.*
AU  - Ruzicka, T.*
AU  - Besch, R.*
C1  - 24438
C2  - 31544
SP  - 919-934
TI  - The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival.
JO  - EMBO Mol. Med.
VL  - 5
IS  - 6
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - no Abstract
AU  - Königshoff, M.
AU  - Schwarz, J.
AU  - Eickelberg, O.
C1  - 6572
C2  - 28884
SP  - 575-577
TI  - Human lung stem cells: Oh, the places you'll go!
JO  - EMBO Mol. Med.
VL  - 3
IS  - 10
PB  - Wiley-VCH
PY  - 2011
SN  - 1757-4676
ER  - 

TY  - JOUR
AB  - Mutations of the mitochondrial PTEN (phosphatase and tensin homologue)-induced kinase1 (PINK1) are important causes of recessive Parkinson disease (PD). Studies on loss of function and overexpression implicate PINK1 in apoptosis, abnormal mitochondrial morphology, impaired dopamine release and motor deficits. However, the fundamental mechanism underlying these various phenotypes remains to be clarified. Using fruit fly and mouse models we show that PINK1 deficiency or clinical mutations impact on the function of Complex I of the mitochondrial respiratory chain, resulting in mitochondrial depolarization and increased sensitivity to apoptotic stress in mammalian cells and tissues. In Drosophila neurons, PINK1 deficiency affects synaptic function, as the reserve pool of synaptic vesicles is not mobilized during rapid stimulation. The fundamental importance of PINK1 for energy maintenance under increased demand is further corroborated as this deficit can be rescued by adding ATP to the synapse. The clinical relevance of our observations is demonstrated by the fact that human wild type PINK1, but not PINK1 containing clinical mutations, can rescue Complex 1 deficiency. Our work suggests that Complex I deficiency underlies, at least partially, the pathogenesis of this hereditary form of PD. As Complex I dysfunction is also implicated in sporadic PD, a convergence of genetic and environmental causes of PD on a similar mitochondrial molecular mechanism appears to emerge.
AU  - Morais, V.*
AU  - Verstreken, P.*
AU  - Roethig, A.
AU  - Smet, J.*
AU  - Snellinx, A.*
AU  - Vanbrabant, M.*
AU  - Haddad, D.*
AU  - Frezza, C.*
AU  - Mandemakers, W.*
AU  - Vogt Weisenhorn, D.M.
AU  - van Coster, R.*
AU  - Wurst, W.
AU  - Scorrano, L.*
AU  - de Strooper, B.*
C1  - 2964
C2  - 26836
SP  - 99-111
TI  - Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function.
JO  - EMBO Mol. Med.
VL  - 1
IS  - 2
PB  - Wiley-VCH
PY  - 2009
SN  - 1757-4676
ER  -