EMBO Molecular Medicine

Our medical research library holds 5 studies published in EMBO Molecular Medicine (2014–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 5 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: EMBO Press
• Published: 2009 to the present, Germany
• Language: English
• ISSN: 1757-4676 (print), 1757-4684 (electronic)
• Its record in the NLM Catalog

2020s

• De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma. D. Xu, Y. Gao, S. Liu, et al. 2025;17(9):2258-2298. PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

  © 2025. The Author(s).

• Pyrimidine addiction: an Achilles' heel of NF2-altered mesothelioma. J. Jia, G.T. Stathopoulos. 2025;17(9):2165-2167. PubMed · Publisher · Free full text

  Abstract

  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.

• KRAS signaling in malignant pleural mesothelioma. A. Marazioti, A.C. Krontira, S.J. Behrend, et al. 2022;14(2):e13631. PubMed · Publisher · Free full text

  Abstract

  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.

  © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

• CXCR4 engagement triggers CD47 internalization and antitumor immunization in a mouse model of mesothelioma. R. Mezzapelle, F. De Marchis, C. Passera, et al. 2021;13(6):e12344. PubMed · Publisher · Free full text

  Abstract

  Boosting antitumor immunity has emerged as a powerful strategy in cancer treatment. While releasing T-cell brakes has received most attention, tumor recognition by T cells is a pre-requisite. Radiotherapy and certain cytotoxic drugs induce the release of damage-associated molecular patterns, which promote tumor antigen cross-presentation and T-cell priming. Antibodies against the "do not eat me" signal CD47 cause macrophage phagocytosis of live tumor cells and drive the emergence of antitumor T cells. Here we show that CXCR4 activation, so far associated only with tumor progression and metastasis, also flags tumor cells to immune recognition. Both CXCL12, the natural CXCR4 ligand, and BoxA, a fragment of HMGB1, promote the release of DAMPs and the internalization of CD47, leading to protective antitumor immunity. We designate as Immunogenic Surrender the process by which CXCR4 turns in tumor cells to macrophages, thereby subjecting a rapidly growing tissue to immunological scrutiny. Importantly, while CXCL12 promotes tumor cell proliferation, BoxA reduces it, and might be exploited for the treatment of malignant mesothelioma and a variety of other tumors.

  © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

2010s

• Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells. I.J. Huijbers, R. Bin Ali, C. Pritchard, et al. 2014;6(2):212-25. PubMed · Publisher · Free full text

  Abstract

  Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.

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