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Dendritic cell cross-dressing and tumor immunity EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-12 Amaia Martinez-Usatorre, Michele De Palma
In addition to direct and cross-presentation, dendritic cells (DCs) can present tumor antigens (TAs) to T cells via a hitherto poorly understood mechanism called “cross-dressing.” DC cross-dressing involves the acquisition of preformed peptide-major histocompatibility class I/II (p-MHC) complexes from cancer cells. This process has been documented both in cell culture and in tumor models; may occur
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TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-05 Anna Scotto Rosato, Einar K Krogsaeter, Dawid Jaślan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Böck, Amanda Wyatt, Daniela Wünkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel
Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality
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TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-03 Alexandre de Nonneville, Sébastien Salas, François Bertucci, Alexander P Sobinoff, José Adélaïde, Arnaud Guille, Pascal Finetti, Jane R Noble, Dimitri Churikov, Max Chaffanet, Elise Lavit, Hilda A Pickett, Corinne Bouvier, Daniel Birnbaum, Roger R Reddel, Vincent Géli
In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these
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Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Marilena Letizia, Yin-Hu Wang, Ulrike Kaufmann, Lorenz Gerbeth, Annegret Sand, Max Brunkhorst, Patrick Weidner, Jörn Felix Ziegler, Chotima Böttcher, Stephan Schlickeiser, Camila Fernández, Megumi Yamashita, Kenneth Stauderman, Katherine Sun, Désirée Kunkel, Murali Prakriya, , Ashley D Sanders, Britta Siegmund, Stefan Feske, Carl Weidinger
Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate
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FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Christopher W Fell, Astrid Hagelkruys, Ana Cicvaric, Marion Horrer, Lucy Liu, Joshua Shing Shun Li, Johannes Stadlmann, Anton A Polyansky, Stefan Mereiter, Miguel Angel Tejada, Tomislav Kokotović, Venkat Swaroop Achuta, Angelica Scaramuzza, Kimberly A Twyman, Michelle M Morrow, Jane Juusola, Huifang Yan, Jingmin Wang, Margit Burmeister, Biswa Choudhury, Thomas Levin Andersen, Gerald Wirnsberger, Uffe
Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and
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Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Michael T Meister, Marian J A Groot Koerkamp, Terezinha de Souza, Willemijn B Breunis, Ewa Frazer-Mendelewska, Mariël Brok, Jeff DeMartino, Freek Manders, Camilla Calandrini, Hinri H D Kerstens, Alex Janse, M Emmy M Dolman, Selma Eising, Karin P S Langenberg, Marc van Tuil, Rutger R G Knops, Sheila Terwisscha van Scheltinga, Laura S Hiemcke-Jiwa, Uta Flucke, Johannes H M Merks, Max M van Noesel, Bastiaan
Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all
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Liquid biopsy: blood-based analyses of circulating cell-free DNA in xenografts EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-29 Isabel Heidrich, Klaus Pantel
The liquid biopsy concept has been introduced for circulating tumor cells more than 10 years ago (Pantel & Alix-Panabieres, 2010) and rapidly extended to cell-free DNA released from tumor cells (ctDNA; Lo et al, 2021) and other tumor-derived products such as circulating cell-free RNA (noncoding and messenger RNA), extracellular vesicles, or tumor-educated platelets (Alix-Panabières & Pantel, 2021)
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SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19 EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-27 Huai-Chia Chuang, Chia-Hsin Hsueh, Pu-Ming Hsu, Rou-Huei Huang, Ching-Yi Tsai, Nai-Hsiang Chung, Yen-Hung Chow, Tse-Hua Tan
ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells was correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2;
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Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-21 Laura Sanchez-Burgos, Belén Navarro-González, Santiago García-Martín, Oleksandra Sirozh, Jorge Mota-Pino, Elena Fueyo-Marcos, Héctor Tejero, Marta Elena Antón, Matilde Murga, Fátima Al-Shahrour, Oscar Fernandez-Capetillo
FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously
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A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-14 Richell Booijink, Fernando Salgado-Polo, Craig Jamieson, Anastassis Perrakis, Ruchi Bansal
The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement
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Is there an unmet medical need for improved hearing restoration? EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-14 Bettina Julia Wolf, Kathrin Kusch, Victoria Hunniford, Barbara Vona, Robert Kühler, Daniel Keppeler, Nicola Strenzke, Tobias Moser
Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health
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A novel platform for attenuating immune hyperactivity using EXO-CD24 in COVID-19 and beyond EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-13 Shiran Shapira, Marina Ben Shimon, Mori Hay-Levi, Gil Shenberg, Guy Choshen, Lian Bannon, Michael Tepper, Dina Kazanov, Jonathan Seni, Shahar Lev-Ari, Michael Peer, Dimitrios Boubas, Justin Stebbing, Sotirios Tsiodras, Nadir Arber
A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs)
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Genetically modified macrophages accelerate myelin repair EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-13 Marie-Stéphane Aigrot, Clara Barthelemy, Sarah Moyon, Gaelle Dufayet-Chaffaud, Leire Izagirre-Urizar, Beatrix Gillet-Legrand, Satoru Tada, Laura Bayón-Cordero, Juan-Carlos Chara, Carlos Matute, Nathalie Cartier, Catherine Lubetzki, Vanja Tepavčević
Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination
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Therapeutic application of PPE2 protein of Mycobacterium tuberculosis in inhibiting tissue inflammation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-11 Ravi Pal, Madhu Babu Battu, Sangita Mukhopadhyay
There is an increasing need to develop biological anti-inflammatory agents that are more targeted, effective, and with lesser side effects as compared to conventional chemical drugs. In the present study, we found that Mycobacterium tuberculosis protein PPE2 and a synthetic derivative peptide can suppress the mast cell population and inhibit several vasoactive and fibrogenic mediators and pro-inflammatory
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Alteration of microbiota antibody-mediated immune selection contributes to dysbiosis in inflammatory bowel diseases EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Eva Michaud, Louis Waeckel, Rémi Gayet, Roman Goguyer-Deschaumes, Blandine Chanut, Fabienne Jospin, Katell Bathany, Magali Monnoye, Coraline Genet, Amelie Prier, Caroline Tokarski, Philippe Gérard, Xavier Roblin, Nicolas Rochereau, Stéphane Paul
Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse-transcytosis, the apical-to-basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan–glycan interaction. Here, we asked whether IgA1 and IgA2-microbiota interactions
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Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Vanessa Monteil, Brett Eaton, Elena Postnikova, Michael Murphy, Benedict Braunsfeld, Ian Crozier, Franz Kricek, Janine Niederhöfer, Alice Schwarzböck, Helene Breid, Stephanie Devignot, Jonas Klingström, Charlotte Thålin, Max J Kellner, Wanda Christ, Sebastian Havervall, Stefan Mereiter, Sylvia Knapp, Anna Sanchez Jimenez, Agnes Bugajska-Schretter, Alexander Dohnal, Christine Ruf, Romana Gugenberger
The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here, we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma
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Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Sebastian J Theobald, Alexander Simonis, Julie M Mudler, Ulrike Göbel, Richard Acton, Viktoria Kohlhas, Marie-Christine Albert, Anna-Maria Hellmann, Jakob J Malin, Sandra Winter, Michael Hallek, Henning Walczak, Phuong-Hien Nguyen, Manuel Koch, Jan Rybniker
Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS-CoV-2 mRNA vaccination primes human monocyte-derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed
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Single-cell transcriptomics reveals a senescence-associated IL-6/CCR6 axis driving radiodermatitis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Mor Paldor, Orr Levkovitch-Siany, Dana Eidelshtein, Revital Adar, Claes D Enk, Yitzhak Marmary, Sharona Elgavish, Yuval Nevo, Hadar Benyamini, Inbar Plaschkes, Shiri Klein, Alex Mali, Stefan Rose-John, Amnon Peled, Eithan Galun, Jonathan H Axelrod
Irradiation-induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA-seq analysis of whole skin-derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence-associated IL-6 and IL-1 signaling, together with IL-17 upregulation
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Strengthening vaccines and medicines manufacturing capabilities in Africa: challenges and perspectives EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-27 AbdulRahman A Saied, Asmaa A Metwally, Manish Dhawan, Om Prakash Choudhary, Hani Aiash
Africa carries a high burden of infectious diseases. Every year, millions of Africans contract tuberculosis, malaria, and many other diseases. Malaria kills hundreds of thousands of children under the age of five years annually. More than 11,000 people died during the 2014–2016 Ebola outbreak in West Africa; still, occasional cases of Ebola, as well as monkeypox, periodically appear in the Democratic
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Systemically targeted cancer immunotherapy and gene delivery using transmorphic particles EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-27 Paladd Asavarut, Sajee Waramit, Keittisak Suwan, Gert J K Marais, Aitthiphon Chongchai, Surachet Benjathummarak, Mariam Al-Bahrani, Paula Vila-Gomez, Matthew Williams, Prachya Kongtawelert, Teerapong Yata, Amin Hajitou
Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumour-targeted
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Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Carolin M Sauer, Katrin Heider, Jelena Belic, Samantha E Boyle, James A Hall, Dominique-Laurent Couturier, Angela An, Aadhitthya Vijayaraghavan, Marika AV Reinius, Karen Hosking, Maria Vias, Nitzan Rosenfeld, James D Brenton
Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA
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Functional divergence of the two Elongator subcomplexes during neurodevelopment EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Monika Gaik, Marija Kojic, Megan R Stegeman, Tülay Öncü-Öner, Anna Kościelniak, Alun Jones, Ahmed Mohamed, Pak Yan Stefanie Chau, Sazia Sharmin, Andrzej Chramiec-Głąbik, Paulina Indyka, Michał Rawski, Anna Biela, Dominika Dobosz, Amanda Millar, Vann Chau, Aycan Ünalp, Michael Piper, Mark C Bellingham, Evan E Eichler, Deborah A Nickerson, Handan Güleryüz, Nour El Hana Abbassi, Konrad Jazgar, Melissa
The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental
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The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Piotr Kobialka, Helena Sabata, Odena Vilalta, Leonor Gouveia, Ana Angulo-Urarte, Laia Muixí, Jasmina Zanoncello, Oscar Muñoz-Aznar, Nagore G Olaciregui, Lucia Fanlo, Anna Esteve-Codina, Cinzia Lavarino, Biola M Javierre, Veronica Celis, Carlota Rovira, Susana López-Fernández, Eulàlia Baselga, Jaume Mora, Sandra D Castillo, Mariona Graupera
Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of
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Targeting the Leukemic stem cell protein machinery by inhibition of mitochondrial pyrimidine synthesis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Elisa Donato, Andreas Trumpp
Acute Myeloid Leukemia is one of the most aggressive blood cancers with a high frequency of relapse. While standard chemotherapy is able to target rapidly proliferating immature blasts, it fails to eradicate slowly proliferating Leukemic Stem Cells. Therefore, new therapeutic strategies that efficiently target LSCs are urgently needed. Recent studies suggest that LSCs have particular metabolic vulnerabilities
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Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-07 Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo
Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD
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Biological foundations of successful bacteriophage therapy EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-27 Carola Venturini, Aleksandra Petrovic Fabijan, Alicia Fajardo Lubian, Stefanie Barbirz, Jonathan Iredell
Bacteriophages (phages) are selective viral predators of bacteria. Abundant and ubiquitous in nature, phages can be used to treat bacterial infections (phage therapy), including refractory infections and those resistant to antibiotics. However, despite an abundance of anecdotal evidence of efficacy, significant hurdles remain before routine implementation of phage therapy into medical practice, including
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Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2 EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-25 Xiaoan Wei, Zeyu Zheng, Zhenhua Feng, Lin Zheng, Siyue Tao, Bingjie Zheng, Bao Huang, Xuyang Zhang, Junhui Liu, Yilei Chen, Wentian Zong, Zhi Shan, Shunwu Fan, Jian Chen, Fengdong Zhao
Sigma-1 receptor (Sigmar1) is a specific chaperone located in the mitochondria-associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated
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Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-17 Marina Chan,Eric C Holland,Taranjit S Gujral
The N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant spike protien strongly induces multiple inflammatory molecules in human peripheral blood mononuclear cells, unaffected by the mutations observed in the NTD. Olverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release.
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ASC nanobodies to counteract the consequences of inflammasome activation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-16 Sahil Adriouch, Pablo Pelegrin
Inflammasomes are multiprotein complexes that signal by oligomerizing the apoptosis speck-like protein with caspase recruitment and activator domain (ASC) and are involved in multiple inflammatory, metabolic and degenerative diseases. Pharmacological targeting of specific inflammasomes with small molecules is leading to the development of novel drugs for most common diseases. The targeting of ASC oligomers
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Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-06 Joan So, Alexander C Lewis, Lorey K Smith, Kym Stanley, Rheana Franich, David Yoannidis, Lizzy Pijpers, Pilar Dominguez, Simon J Hogg, Stephin J Vervoort, Fiona C Brown, Ricky W Johnstone, Gabrielle McDonald, Danielle B Ulanet, Josh Murtie, Emily Gruber, Lev M Kats
The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid
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A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-05 Elizabeth A Kuczynski, Giulia Morlino, Alison Peter, Anna M L Coenen-Stass, Jennifer I Moss, Neha Wali, Oona Delpuech, Avinash Reddy, Anisha Solanki, Charles Sinclair, Dinis P Calado, Larissa S Carnevalli
Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl) through immune-competent mice. Lymphoma cells were identified
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Feed-forward loops between metastatic cancer cells and their microenvironment—the stage of escalation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-04 Zora Baumann, Priska Auf der Maur, Mohamed Bentires-Alj
Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental
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Liver gene therapy with intein-mediated F8 trans-splicing corrects mouse haemophilia A EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-02 Federica Esposito, Hristiana Lyubenova, Patrizia Tornabene, Stefano Auricchio, Antonella Iuliano, Edoardo Nusco, Simone Merlin, Cristina Olgasi, Giorgia Manni, Marco Gargaro, Francesca Fallarino, Antonia Follenzi, Alberto Auricchio
Liver gene therapy with adeno-associated viral (AAV) vectors is under clinical investigation for haemophilia A (HemA), the most common inherited X-linked bleeding disorder. Major limitations are the large size of the F8 transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti-F8 antibodies which neutralise F8 activity. Taking advantage of
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Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-02 Nathalie Tisch, Carolin Mogler, Ana Stojanovic, Robert Luck, Emilia A Korhonen, Alexander Ellerkmann, Heike Adler, Mahak Singhal, Géza Schermann, Lena Erkert, Jay V Patankar, Andromachi Karakatsani, Anna-Lena Scherr, Yaron Fuchs, Adelheid Cerwenka, Stefan Wirtz, Bruno Christian Köhler, Hellmut G Augustin, Christoph Becker, Thomas Schmidt, Carmen Ruiz de Almodóvar
The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase-8 as a pro-survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ-specific
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Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Damien Bertheloot, Carlos WS Wanderley, Ayda H Schneider, Lisa DJ Schiffelers, Jennifer D Wuerth, Jan MP Tödtmann, Salie Maasewerd, Ibrahim Hawwari, Fraser Duthie, Cornelia Rohland, Lucas S Ribeiro, Lea-Marie Jenster, Nathalia Rosero, Yonas M Tesfamariam, Fernando Q Cunha, Florian I Schmidt, Bernardo S Franklin
Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron-sized “specks” to maximize caspase-1 activation and the maturation of IL-1 cytokines. Caspase-1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space. ASC specks are released among
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When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Magdalena Wit,Jonathan Trujillo-Viera,Akim Strohmeyer,Martin Klingenspor,Mohammed Hankir,Grzegorz Sumara
The regular overconsumption of energy-dense foods (rich in lipids and sugars) results in elevated intestinal nutrient absorption and consequently excessive accumulation of lipids in the liver, adipose tissue, skeletal muscles, and other organs. This can eventually lead to obesity and obesity-associated diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular
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BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection? EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Abbass Darwich,Chiara Pozzi,Giulia Fornasa,Michela Lizier,Elena Azzolini,Ilaria Spadoni,Francesco Carli,Antonio Voza,Antonio Desai,Carlo Ferrero,Luca Germagnoli,,Alberto Mantovani,Maria Rescigno
Vaccination against an airborne pathogen is very effective if it induces also the development of mucosal antibodies that can protect against infection. The mRNA-based vaccine-encoding SARS-CoV-2 full-length spike protein (BNT162b2, Pfizer/BioNTech) protects also against infection despite being administered systemically. Here, we show that upon vaccination, cognate IgG molecules are also found in the
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AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Karima Habbas,Oktay Cakil,Boglárka Zámbó,Ricardos Tabet,Fabrice Riet,Doulaye Dembele,Jean-Louis Mandel,Michaël Hocquemiller,Ralph Laufer,Françoise Piguet,Hervé Moine
Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator
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The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Julia Ring,Jelena Tadic,Selena Ristic,Michael Poglitsch,Martina Bergmann,Nemanja Radic,Dirk Mossmann,YongTian Liang,Marta Maglione,Andrea Jerkovic,Roozbeh Hajiraissi,Marcel Hanke,Victoria Küttner,Heimo Wolinski,Andreas Zimmermann,Lana Domuz Trifunović,Leonie Mikolasch,Daiana N Moretti,Filomena Broeskamp,Julia Westermayer,Claudia Abraham,Simon Schauer,Christopher Dammbrueck,Sebastian J Hofer,Mahmoud
Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor
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Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Jessica Giehrl-Schwab,Florian Giesert,Benedict Rauser,Chu Lan Lao,Sina Hembach,Sandrine Lefort,Ignacio L Ibarra,Christina Koupourtidou,Malte Daniel Luecken,Dong-Jiunn Jeffery Truong,Judith Fischer-Sternjak,Giacomo Masserdotti,Nilima Prakash,Jovica Ninkovic,Sabine M Hölter,Daniela M Vogt Weisenhorn,Fabian J Theis,Magdalena Götz,Wolfgang Wurst
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
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S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-01 Fuying Chen,Cheng Ni,Xiaoxiao Wang,Ruhong Cheng,Chaolan Pan,Yumeng Wang,Jianying Liang,Jia Zhang,Jinke Cheng,Y Eugene Chin,Yi Zhou,Zhen Wang,Yiran Guo,She Chen,Stephanie Htun,Erin F Mathes,Alejandra G de Alba Campomanes,Anne M Slavotinek,Si Zhang,Ming Li,Zhirong Yao
In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis-like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane-bound transcription factor peptidase/site-1 protease (MBTPS1
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SARS-CoV-2 spike spurs intestinal inflammation via VEGF production in enterocytes. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Fa-Min Zeng,Ying-Wen Li,Zhao-Hua Deng,Jian-Zhong He,Wei Li,Lijie Wang,Ting Lyu,Zhanyu Li,Chaoming Mei,Meiling Yang,Yingying Dong,Guan-Min Jiang,Xiaofeng Li,Xi Huang,Fei Xiao,Ye Liu,Hong Shan,Huanhuan He
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can cause gastrointestinal (GI) symptoms that often correlate with the severity of COVID-19. Here, we explored the pathogenesis underlying the intestinal inflammation in COVID-19. Plasma VEGF level was particularly elevated in patients with GI symptoms and significantly correlated with intestinal edema and disease progression. Through an
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AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-30 Marika Marino,Lujia Zhou,Melvin Y Rincon,Zsuzsanna Callaerts-Vegh,Jens Verhaert,Jérôme Wahis,Eline Creemers,Lidia Yshii,Keimpe Wierda,Takashi Saito,Catherine Marneffe,Iryna Voytyuk,Yessica Wouters,Maarten Dewilde,Sandra I Duqué,Cécile Vincke,Yona Levites,Todd E Golde,Takaomi C Saido,Serge Muyldermans,Adrian Liston,Bart De Strooper,Matthew G Holt
Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood-brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated
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CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-17 Antoine de Zélicourt,Abdallah Fayssoil,Mbarka Dakouane-Giudicelli,Isley De Jesus,Ahmed Karoui,Faouzi Zarrouki,Florence Lefebvre,Arnaud Mansart,Jean-Marie Launay,Jerome Piquereau,Mariana G Tarragó,Marcel Bonay,Anne Forand,Sophie Moog,France Piétri-Rouxel,Elise Brisebard,Claudia C S Chini,Sonu Kashyap,Matthew J Fogarty,Gary C Sieck,Mathias Mericskay,Eduardo N Chini,Ana Maria Gomez,José-Manuel Cancela
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase-producing modulators of Ca2+ signaling
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Autologous, lentivirus-modified, T-rapa cell "micropharmacies" for lysosomal storage disorders. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-17 Murtaza S Nagree,Tania C Felizardo,Mary L Faber,Jitka Rybova,C Anthony Rupar,S Ronan Foley,Maria Fuller,Daniel H Fowler,Jeffrey A Medin
T cells are the current choice for many cell therapy applications. They are relatively easy to access, expand in culture, and genetically modify. Rapamycin-conditioning ex vivo reprograms T cells, increasing their memory properties and capacity for survival, while reducing inflammatory potential and the amount of preparative conditioning required for engraftment. Rapamycin-conditioned T cells have
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RNAi to treat SARS-CoV-2-variant proofing the next generation of therapies. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-14 Nigel A J McMillan,Kevin V Morris,Adi Idris
There is an urgent need to bring new antivirals to SARS-CoV-2 to the market. Indeed, in the last 3 months, we have seen at least two new antivirals approved, molnupiravir and paxlovid. Both are older established antivirals that show some efficacy against SARS-CoV-2. The work by Chang et al (2022) in the current issue of EMBO Molecular Medicine explores the use of short interfering RNAs to directly
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Patient-derived organoids, creating a new window of opportunities for pancreatic cancer patients. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-14 Sandhya Sandhya,Tara L Hogenson,Martin E Fernandez-Zapico
Standard-of-care regimens for pancreatic ductal adenocarcinoma (PDAC) include a combination of chemotherapies, which are associated with toxicity and eventually tumor resistance. The lack of relevant tool to identify and evaluate new therapies in PDAC necessitates the search for a model, especially for cases with treatment resistance to standard of care. In the study from Peschke et al (2022), they
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Angpt2/Tie2 autostimulatory loop controls tumorigenesis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-10 Ninelia Minaskan Karabid,Tobias Wiedemann,Sebastian Gulde,Hermine Mohr,Renu Chandra Segaran,Julia Geppert,Maria Rohm,Giovanni Vitale,Germano Gaudenzi,Alessandra Dicitore,Donna Pauler Ankerst,Yiyao Chen,Rickmer Braren,Georg Kaissis,Franz Schilling,Mathias Schillmaier,Graeme Eisenhofer,Stephan Herzig,Federico Roncaroli,Jürgen B Honegger,Natalia S Pellegata
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Promoters of ASCL1- and NEUROD1-dependent genes are specific targets of lurbinectedin in SCLC cells. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-09 Federico Costanzo,Marta Martínez Diez,Gema Santamaría Nuñez,Juan Ignacio Díaz-Hernandéz,Carlos Mario Genes Robles,Javier Díez Pérez,Emmanuel Compe,Romeo Ricci,Tsai-Kun Li,Frédéric Coin,Juan Fernando Martínez Leal,Eva Maria Garrido-Martin,Jean Marc Egly
Small-Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according
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Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-07 Liping Ye,Chuyong Lin,Xi Wang,Qiji Li,Yue Li,Meng Wang,Zekun Zhao,Xianqiu Wu,Dongni Shi,Yunyun Xiao,Liangliang Ren,Yunting Jian,Meisongzhu Yang,Ruizhang Ou,Guangzheng Deng,Ying Ouyang,Xiangfu Chen,Jun Li,Libing Song
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CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-03-07 Lixiazi He,Christian Arnold,Judith Thoma,Christian Rohde,Maksim Kholmatov,Swati Garg,Cheng-Chih Hsiao,Linda Viol,Kaiqing Zhang,Rui Sun,Christina Schmidt,Maike Janssen,Tara MacRae,Karin Huber,Christian Thiede,Josée Hébert,Guy Sauvageau,Julia Spratte,Herbert Fluhr,Gabriela Aust,Carsten Müller-Tidow,Christof Niehrs,Gislene Pereira,Jörg Hamann,Motomu Tanaka,Judith B Zaugg,Caroline Pabst
The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained
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COVID-19 vaccination, time for a second breath? EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-25 Christiane E Gerke,Bernd Pulverer,Philippe J Sansonetti
One year into the Covid-19 vaccination campaign, C. Gerke, B. Pulverer and P. Sansonetti discuss its results and redefine its objectives.
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Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-22 Zehra Yildirim, Sabyasachi Baboo, Syed M Hamid, Asli E Dogan, Ozlem Tufanli, Sabrina Robichaud, Christina Emerton, Jolene K Diedrich, Hasan Vatandaslar, Fotis Nikolos, Yanghong Gu, Takao Iwawaki, Elizabeth Tarling, Mireille Ouimet, David L Nelson, John R Yates, Peter Walter, Ebru Erbay
Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring
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A siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-21 Yi-Chung Chang, Chi-Fan Yang, Yi-Fen Chen, Chia-Chun Yang, Yuan-Lin Chou, Hung-Wen Chou, Tein-Yao Chang, Tai-Ling Chao, Shu-Chen Hsu, Si-Man Ieong, Ya-Min Tsai, Ping-Cheng Liu, Yuan-Fan Chin, Jun-Tung Fang, Han-Chieh Kao, Hsuan-Ying Lu, Jia-Yu Chang, Ren-Shiuan Weng, Qian-Wen Tu, Fang-Yu Chang, Kuo-Yen Huang, Tong-Young Lee, Sui-Yuan Chang, Pan-Chyr Yang
The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on the long-term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2
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Ketone body oxidation increases cardiac endothelial cell proliferation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-18 Eva-Maria Weis, Patrycja Puchalska, Alisa B Nelson, Jacqueline Taylor, Iris Moll, Sana S Hasan, Matthias Dewenter, Marco Hagenmüller, Thomas Fleming, Gernot Poschet, Agnes Hotz-Wagenblatt, Johannes Backs, Peter A Crawford, Andreas Fischer
Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial
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A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-17 Lucía Zhu, Diana Retana, Pedro García-Gómez, Laura Álvaro-Espinosa, Neibla Priego, Mariam Masmudi-Martín, Natalia Yebra, Lauritz Miarka, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Sonia Martínez, Cecilia Sobrino, Nuria Ajenjo, Maria-Jesus Artiga, Eva Ortega-Paino, Raúl Torres-Ruiz, Sandra Rodríguez-Perales, , Riccardo Soffietti, Luca Bertero, Paola Cassoni, Tobias Weiss, Javier Muñoz, Juan Manuel
We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases
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Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-16 Julia Zinngrebe, Barbara Moepps, Thomas Monecke, Peter Gierschik, Ferdinand Schlichtig, Thomas F E Barth, Gudrun Strauß, Elena Boldrin, Carsten Posovszky, Ansgar Schulz, Ortraud Beringer, Eva Rieser, Eva-Maria Jacobsen, Myriam Ricarda Lorenz, Klaus Schwarz, Ulrich Pannicke, Henning Walczak, Dierk Niessing, Catharina Schuetz, Pamela Fischer-Posovszky, Klaus-Michael Debatin
Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss-of-function variants in the OTU-deubiquitinase OTULIN suffer from neonatal-onset OTULIN-related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here
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Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-14 Serena Diazzi, Alberto Baeri, Julien Fassy, Margaux Lecacheur, Oskar Marin-Bejar, Christophe A Girard, Lauren Lefevre, Caroline Lacoux, Marie Irondelle, Carine Mounier, Marin Truchi, Marie Couralet, Mickael Ohanna, Alexandrine Carminati, Ilona Berestjuk, Frederic Larbret, David Gilot, Georges Vassaux, Jean-Christophe Marine, Marcel Deckert, Bernard Mari, Sophie Tartare-Deckert
Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma
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Seasonality of influenza and other respiratory viruses EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-14 Gabriele Neumann, Yoshihiro Kawaoka
In virology, the term seasonality describes variations in virus prevalence at more or less regular intervals throughout the year. Specifically, it has long been recognized that outbreaks of human influenza viruses, respiratory syncytial virus (RSV), and human coronaviruses occur in temperate climates during the winter season, whereas low activity is detected during the summer months. Other human respiratory
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Antifibrotic drugs as therapeutic tools in resistant melanoma EMBO Mol. Med. (IF 14.26) Pub Date : 2022-02-14 Berta Sanchez-Laorden, M Angela Nieto
Melanoma is the most aggressive form of skin cancer. Together with the recent advances in immunotherapy, targeted therapy with inhibitors of the Mitogen Activated Protein Kinase (MAPKi) pathway including BRAF and MEK inhibitors has greatly improved the clinical outcome of these patients. Unfortunately, due to genetic and non-genetic events, many patients develop resistance to MAPKi. Melanoma phenotypic