{"title":"FOXK2 in skeletal muscle development: a new pathogenic gene for congenital myopathy with ptosis.","authors":"Peixuan Wu,Nan Song,Yang Xiang,Zhe Tao,Bing Mao,Ruochen Guo,Xin Wang,Dan Wu,Zhenzhen Zhang,Xin Chen,Duan Ma,Tianyu Zhang,Bingtao Hao,Jing Ma","doi":"10.1038/s44321-025-00247-x","DOIUrl":"https://doi.org/10.1038/s44321-025-00247-x","url":null,"abstract":"Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2-deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"33 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nieves Fernández-Gallego,Blanca Anega,Susana Luengo-Arias,Maider Bizkarguenaga,Rubén Gil-Redondo,Nieves Embade,Laura Navarrete-Arias,Marta Ramírez-Huesca,Emigdio Álvarez-Corrales,Sara G Dosil,Raquel Castillo-González,Amelia Rojas-Gomez,Inés Espeleta,Sara Martínez-Martínez,Arantzazu Alfranca,Virginia G de Yebenes,Noa Beatriz Martín-Cófreces,Julián Aragonés,Pilar Martin,Oscar Millet,Francisco Sánchez-Madrid,Danay Cibrian
{"title":"Restricting SLC7A5-mediated Leucine uptake in T cells prevents acute GVHD and maintains GVT response.","authors":"Nieves Fernández-Gallego,Blanca Anega,Susana Luengo-Arias,Maider Bizkarguenaga,Rubén Gil-Redondo,Nieves Embade,Laura Navarrete-Arias,Marta Ramírez-Huesca,Emigdio Álvarez-Corrales,Sara G Dosil,Raquel Castillo-González,Amelia Rojas-Gomez,Inés Espeleta,Sara Martínez-Martínez,Arantzazu Alfranca,Virginia G de Yebenes,Noa Beatriz Martín-Cófreces,Julián Aragonés,Pilar Martin,Oscar Millet,Francisco Sánchez-Madrid,Danay Cibrian","doi":"10.1038/s44321-025-00250-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00250-2","url":null,"abstract":"The L-Leu amino acid transporter SLC7A5 has become an important target in inflammation and cancer. However, its role in acute graft-versus-host disease (aGVHD) and graft versus tumor (GVT) remains unexplored. We demonstrate that SLC7A5 deletion affected T cell activation, expansion and survival, and reduced IFNγ and granzyme B expression, thus controlling aGVHD, but without effect on tumor growth. On the other hand, dietary restriction of L-Leu reduced aGVHD by controlling T cell expansion, inducing apoptosis, and affecting granzyme B secretion. However, CD8 T cells did not fail to activate and express IFNγ in the absence of L-Leu, and showed an increased proportion of central memory T cells, which contributed to the GVT response. Deletion of SLC7A5 in T cells compromises mTORC1, glycolysis and mitochondrial oxidation. On the contrary, L-Leu removal reduced mTORC1 and completely blocked glycolysis but preserved mitochondrial function, favoring the generation of central memory responses and expression of stemness marker TCF1. In addition, our metabolomics data underscores the L-Leu-derived metabolite β-hydroxybutyrate as an important marker for SLC7A5-dependent allogenic T cell expansion in aGVHD.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"4 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah Dallel,Manon Despalles,Margaux Tore,Yoan Renaud,Ayhan Kocer,Christelle Damon-Soubeyrand,Pierre Pouchin,Caroline Vachias,Katia Boutourlinsky,Céline Gonthier-Gueret,Angélique De Haze,Phelipe Sanchez,Jean-Christophe Pointud,Erwan Bouchareb,Marine Vialat,Aurélie Lagarde,Cristina Gulunga,Laure Chaput,Aurélie Vega,Florence Brugnon,Igor Tauveron,Amalia Trousson,Cyrille de Joussineau,Françoise Degoul,Laurent Morel,Jean Marc Lobaccaro,Salwan Maqdasy,Silvère Baron
{"title":"LXR pathway drives hormonal response intensity in polycystic ovary syndrome.","authors":"Sarah Dallel,Manon Despalles,Margaux Tore,Yoan Renaud,Ayhan Kocer,Christelle Damon-Soubeyrand,Pierre Pouchin,Caroline Vachias,Katia Boutourlinsky,Céline Gonthier-Gueret,Angélique De Haze,Phelipe Sanchez,Jean-Christophe Pointud,Erwan Bouchareb,Marine Vialat,Aurélie Lagarde,Cristina Gulunga,Laure Chaput,Aurélie Vega,Florence Brugnon,Igor Tauveron,Amalia Trousson,Cyrille de Joussineau,Françoise Degoul,Laurent Morel,Jean Marc Lobaccaro,Salwan Maqdasy,Silvère Baron","doi":"10.1038/s44321-025-00251-1","DOIUrl":"https://doi.org/10.1038/s44321-025-00251-1","url":null,"abstract":"Gonadotropin injections used to stimulate oocyte production during assisted reproductive technology (ART) procedures are associated with the risk of an abnormal response in predisposed patients suffering polycystic ovary syndrome (PCOS). Liver X receptors (LXR) pathway has been identified as key regulators during this process. This study explores the integration of the hormonal signals, cellular networks and molecular mechanisms linking sterol signaling with inflammation and immune infiltration. Pharmacological activation of LXR in a wild-type context protects against gonadotropin hyperstimulation mirroring the effect observed in LXR-deficient mice. Ovarian stimulation leads to immune cell infiltration orchestrated by granulosa cells in absence of LXR, resulting in an altered granulosa cell response to gonadotropin and enhanced inflammation. LXR controls inflammasome activity by regulating Thioredoxin Interacting Protein (TXNIP) gene expression in mural granulosa cells, thereby modulating IL1β production. This immune cell infiltration persists throughout ovulation in PCOS patients and is observed in cumulus oocytes complexes, highlighting the pivotal role of LXR path in regulating inflammatory processes during hormonal stimulation in ART procedures.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"115 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marie G Robert,Christopher Swale,Belen Pachano,Léa Dépéry,Valeria Bellini,Céline Dard,Dominique Cannella,Charlotte Corrao,Lucid Belmudes,Yohann Couté,Alexandre Bougdour,Hervé Pelloux,Emmanuelle Chapey,Martine Wallon,Marie-Pierre Brenier-Pinchart,Mohamed-Ali Hakimi
{"title":"Uncovering biomarkers for chronic toxoplasmosis detection highlights alternative pathways shaping parasite dormancy.","authors":"Marie G Robert,Christopher Swale,Belen Pachano,Léa Dépéry,Valeria Bellini,Céline Dard,Dominique Cannella,Charlotte Corrao,Lucid Belmudes,Yohann Couté,Alexandre Bougdour,Hervé Pelloux,Emmanuelle Chapey,Martine Wallon,Marie-Pierre Brenier-Pinchart,Mohamed-Ali Hakimi","doi":"10.1038/s44321-025-00252-0","DOIUrl":"https://doi.org/10.1038/s44321-025-00252-0","url":null,"abstract":"Toxoplasma gondii, a neurotropic protozoan, causes toxoplasmosis, a prevalent zoonotic and food-borne infection, posing significant risks to immunocompromised individuals and congenital cases. The chronic phase, characterized by dormant, cyst-forming bradyzoites, is central to disease progression but is poorly understood due to the lack of serological tests to detect bradyzoite-specific antigens. This study identifies the bradyzoite serological marker (BSM) and cyst-associated BCLA as effective biomarkers for chronic toxoplasmosis. These markers showed high sensitivity and specificity in detecting cyst-bearing mice and had a positivity rate of 30% in humans with prior immunity. Bradyzoite serology helps to discriminate between recent and past infections, with BCLA improving the accuracy of the diagnosis of congenital infections. Mechanistic analyses show that the chromatin modifiers MORC and HDAC3 epistatically regulate BFD1, a key bradyzoite regulator. While BFD1 controls the expression of bradyzoite genes such as BCLA, a specific subset, including BSM, is regulated independently of BFD1. This multilayered regulation complicates the understanding of parasite persistence in humans, but offers promise for improved serologic diagnosis during pregnancy, but also in individuals with mental illness.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"14 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition.","authors":"Gabriel Morin,Alexandre P Garneau,Nabiha Bouzakher,Louise Ségot,Antoine Fraissenon,Amélie Blondel,Florence Petit,Caroline Chopinet,Franck Mayeux,Pierre Fayoux,Anne Dompmartin,Christine Bodemer,Estelle Balducci,Sophie Kaltenbach,Patrick Villarese,Vahid Asnafi,Christophe Legendre,Christine Broissand,Sylvie Fraitag,Chloé Quelin,Nicolas Goudin,Laurent Guibaud,Guillaume Canaud","doi":"10.1038/s44321-025-00249-9","DOIUrl":"https://doi.org/10.1038/s44321-025-00249-9","url":null,"abstract":"Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. Currently, there are no approved treatments specifically dedicated to patients with PIK3R1 mutations, and medical care primarily focuses on managing symptoms. In this study, we identified three patients, including two children, who had mosaic somatic PIK3R1 mutations affecting the iSH2 domain, along with severe associated symptoms that were unsuccessfully treated with rapamycin. We conducted in vitro experiments to investigate the impact of these mutations, including a double PIK3R1 mutation in cis observed in one patient. Our findings revealed that p85α mutants in the iSH2 domain showed sensitivity to alpelisib, a pharmacological inhibitor of PI3Kα. Based on these findings, we received authorization to administer alpelisib to all three patients. Following drug introduction, patients rapidly demonstrated clinical improvement, pain, fatigue and inflammatory flares were attenuated. Magnetic Resonance Imaging showed a mean decrease of 22.67% in the volume of vascular malformations over twelve months of treatment with alpelisib. No drug-related adverse events were reported during the course of the study. In conclusion, this study provides support for the use of PI3Kα inhibition as a promising therapeutic approach for individuals with PIK3R1-related anomalies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"73 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hao Liu,Nan Liu,Chen Zhou,Ailing Du,Mayank Kapadia,Phillip W L Tai,Erik Barton,Guangping Gao,Dan Wang
{"title":"High-purity AAV vector production utilizing recombination-dependent minicircle formation and genetic coupling.","authors":"Hao Liu,Nan Liu,Chen Zhou,Ailing Du,Mayank Kapadia,Phillip W L Tai,Erik Barton,Guangping Gao,Dan Wang","doi":"10.1038/s44321-025-00248-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00248-w","url":null,"abstract":"Triple transfection of HEK293 cells is the most widely used method for producing recombinant adeno-associated virus (rAAV), a leading gene delivery vector for human gene therapy. Despite its tremendous success, this approach generates several vector-related impurities that could potentially compromise the safety and potency of rAAV. In this study, we introduce a method for high-purity AAV vector production utilizing recombination-dependent minicircle formation and genetic coupling (AAVPureMfg). Compared with traditional triple transfection, AAVPureMfg substantially improves vector purity by reducing prokaryotic DNA contaminants by 10- to 50-fold and increasing the full capsid ratio up to threefold. Mechanistically, Bxb1-mediated excision of the transgene cassette generates a minicircle cis construct devoid of bacterial sequences and ensures synchronized colocalization of trans and cis constructs in productive cells. Furthermore, we developed iterations that enhance vector genome homogeneity and streamline the production of rAAV with various transgenes, serotypes, and ITR configurations. Overall, our findings demonstrate that AAVPureMfg overcomes the inherent limitations associated with triple transfection, offering a broadly applicable and easy-to-implement method for producing high-purity rAAV with reduced plasmid costs.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"61 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nadja Rotte, Jessica E M Dunleavy, Michelle D Runkel, Lina Bosse, Daniela Fietz, Adrian Pilatz, Johanna Kuss, Ann-Kristin Dicke, Sofia B Winge, Sara Di Persio, Christian Ruckert, Verena Nordhoff, Hans-Christian Schuppe, Kristian Almstrup, Sabine Kliesch, Nina Neuhaus, Birgit Stallmeyer, Moira K O'Bryan, Frank Tüttelmann, Corinna Friedrich
{"title":"Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes.","authors":"Nadja Rotte, Jessica E M Dunleavy, Michelle D Runkel, Lina Bosse, Daniela Fietz, Adrian Pilatz, Johanna Kuss, Ann-Kristin Dicke, Sofia B Winge, Sara Di Persio, Christian Ruckert, Verena Nordhoff, Hans-Christian Schuppe, Kristian Almstrup, Sabine Kliesch, Nina Neuhaus, Birgit Stallmeyer, Moira K O'Bryan, Frank Tüttelmann, Corinna Friedrich","doi":"10.1038/s44321-025-00244-0","DOIUrl":"https://doi.org/10.1038/s44321-025-00244-0","url":null,"abstract":"<p><p>Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency (N = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP. Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bee Hui Liu, Miao Liu, Sridhar Radhakrishnan, Meng-Yuan Dai, Chaitanya Kumar Jaladanki, Chong Gao, Jing Ping Tang, Kalpana Kumari, Mei Lin Go, Kim Anh L Vu, Junsu Kwon, Hyuk-Soo Seo, Kijun Song, Xi Tian, Li Feng, Justin L Tan, Arek V Melkonian, Zhaoji Liu, Gerburg Wulf, Haribabu Arthanari, Jun Qi, Sirano Dhe-Paganon, John G Clohessy, Yeu Khai Choong, J Sivaraman, Hao Fan, Daniel G Tenen, Li Chai
{"title":"Targeting transcription factors through an IMiD independent zinc finger domain.","authors":"Bee Hui Liu, Miao Liu, Sridhar Radhakrishnan, Meng-Yuan Dai, Chaitanya Kumar Jaladanki, Chong Gao, Jing Ping Tang, Kalpana Kumari, Mei Lin Go, Kim Anh L Vu, Junsu Kwon, Hyuk-Soo Seo, Kijun Song, Xi Tian, Li Feng, Justin L Tan, Arek V Melkonian, Zhaoji Liu, Gerburg Wulf, Haribabu Arthanari, Jun Qi, Sirano Dhe-Paganon, John G Clohessy, Yeu Khai Choong, J Sivaraman, Hao Fan, Daniel G Tenen, Li Chai","doi":"10.1038/s44321-025-00241-3","DOIUrl":"10.1038/s44321-025-00241-3","url":null,"abstract":"<p><p>Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dana Krauß,Veronica Moreno-Viedma,Emi Adachi-Fernandez,Cristiano de Sá Fernandes,Jakob-Wendelin Genger,Ourania Fari,Bernadette Blauensteiner,Dominik Kirchhofer,Nikolina Bradaric,Valeriya Gushchina,Georgios Fotakis,Thomas Mohr,Ifat Abramovich,Inbal Mor,Martin Holcmann,Andreas Bergthaler,Arvand Haschemi,Zlatko Trajanoski,Juliane Winkler,Eyal Gottlieb,Maria Sibilia
{"title":"EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer.","authors":"Dana Krauß,Veronica Moreno-Viedma,Emi Adachi-Fernandez,Cristiano de Sá Fernandes,Jakob-Wendelin Genger,Ourania Fari,Bernadette Blauensteiner,Dominik Kirchhofer,Nikolina Bradaric,Valeriya Gushchina,Georgios Fotakis,Thomas Mohr,Ifat Abramovich,Inbal Mor,Martin Holcmann,Andreas Bergthaler,Arvand Haschemi,Zlatko Trajanoski,Juliane Winkler,Eyal Gottlieb,Maria Sibilia","doi":"10.1038/s44321-025-00240-4","DOIUrl":"https://doi.org/10.1038/s44321-025-00240-4","url":null,"abstract":"Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"14 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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