Pub Date : 2025-12-22DOI: 10.1038/s44321-025-00359-4
Mark R Woodford,Dimitra Bourboulia,Mehdi Mollapour
{"title":"c-KIT joins the TSC ToolKIT: a new driver of renal cystogenesis.","authors":"Mark R Woodford,Dimitra Bourboulia,Mehdi Mollapour","doi":"10.1038/s44321-025-00359-4","DOIUrl":"https://doi.org/10.1038/s44321-025-00359-4","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"22 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807885","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}
Pub Date : 2025-12-19DOI: 10.1038/s44321-025-00358-5
Márcio Augusto Campos-Ribeiro,Erminia Donnarumma,Hendrik Nolte,Paul Cobine,Elodie Vimont,Dusanka Milenkovic,Juan Diego Hernandez-Camacho,Francina Langa-Vives,Etienne Kornobis,Esthel Pénard,Sonny Yde,Thomas Langer,Véronique Paquis-Flucklinger,Timothy Wai
Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.
{"title":"Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.","authors":"Márcio Augusto Campos-Ribeiro,Erminia Donnarumma,Hendrik Nolte,Paul Cobine,Elodie Vimont,Dusanka Milenkovic,Juan Diego Hernandez-Camacho,Francina Langa-Vives,Etienne Kornobis,Esthel Pénard,Sonny Yde,Thomas Langer,Véronique Paquis-Flucklinger,Timothy Wai","doi":"10.1038/s44321-025-00358-5","DOIUrl":"https://doi.org/10.1038/s44321-025-00358-5","url":null,"abstract":"Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785821","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}
Pub Date : 2025-12-19DOI: 10.1038/s44321-025-00352-x
Søren H Hough,Satpal S Jhujh,Samah W Awwad,Oliver E Lewis,Simon Lam,John C Thomas,Thorsten Mosler,Aldo Bader,Lauren Bartik,Shane McKee,Shivarajan Amudhavalli,Estelle Colin,Nadirah Damseh,Emma Clement,Pilar Cacheiro,Anirban Majumdar,Damian Smedley,Joël Fluss,Rosalinda Giannini,Isabelle Thiffault,Guido Zagnoli Vieira,Rimma Belotserkovskaya,Stephen J Smerdon,Petra Beli,Yaron Galanty,Christopher J Carnie,Grant S Stewart,Stephen P Jackson
Ubiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRISPR-Cas9 knockout screen focused on ubiquitin E3 ligases and related proteins with the DNA topoisomerase I inhibitor camptothecin. This led us to establish that MAEA, a core subunit of the CTLH E3 ligase complex, is a critical regulator of homologous recombination and the replication stress response. In tandem, we identified eight patients with variants in MAEA who present with a neurodevelopmental disorder that we term DIADEM (Developmental delay and Intellectual disability Associated with DEfects in MAEA). Analysis of patient-derived cell lines and mutation modeling reveal an underlying defect in HR-dependent DNA repair and replication fork restart and protection as a likely cause of disease. Mechanistically, we find that MAEA dysfunction hinders DNA repair by reducing the efficiency of RAD51 loading at sites of DNA damage, which we propose may contribute to the presentation of DIADEM by compromising genome integrity and cell division during development.
{"title":"Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay.","authors":"Søren H Hough,Satpal S Jhujh,Samah W Awwad,Oliver E Lewis,Simon Lam,John C Thomas,Thorsten Mosler,Aldo Bader,Lauren Bartik,Shane McKee,Shivarajan Amudhavalli,Estelle Colin,Nadirah Damseh,Emma Clement,Pilar Cacheiro,Anirban Majumdar,Damian Smedley,Joël Fluss,Rosalinda Giannini,Isabelle Thiffault,Guido Zagnoli Vieira,Rimma Belotserkovskaya,Stephen J Smerdon,Petra Beli,Yaron Galanty,Christopher J Carnie,Grant S Stewart,Stephen P Jackson","doi":"10.1038/s44321-025-00352-x","DOIUrl":"https://doi.org/10.1038/s44321-025-00352-x","url":null,"abstract":"Ubiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRISPR-Cas9 knockout screen focused on ubiquitin E3 ligases and related proteins with the DNA topoisomerase I inhibitor camptothecin. This led us to establish that MAEA, a core subunit of the CTLH E3 ligase complex, is a critical regulator of homologous recombination and the replication stress response. In tandem, we identified eight patients with variants in MAEA who present with a neurodevelopmental disorder that we term DIADEM (Developmental delay and Intellectual disability Associated with DEfects in MAEA). Analysis of patient-derived cell lines and mutation modeling reveal an underlying defect in HR-dependent DNA repair and replication fork restart and protection as a likely cause of disease. Mechanistically, we find that MAEA dysfunction hinders DNA repair by reducing the efficiency of RAD51 loading at sites of DNA damage, which we propose may contribute to the presentation of DIADEM by compromising genome integrity and cell division during development.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785822","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}
Pub Date : 2025-12-19DOI: 10.1038/s44321-025-00361-w
Jianfeng Ge,Shoko Hirosue,Leticia Castillon,Saroor A Patel,Ludovic Wesolowski,Anna Dyas,Cissy Yong,Sanne de Haan,Jarno Drost,Grant D Stewart,Anna C Obenauf,Daniel Muñoz-Espín,Sakari Vanharanta
The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.
von Hippel-Lindau肿瘤抑制因子（VHL）是泛素连接酶复合物的一个组成部分，控制细胞对缺氧的反应。内源性VHL也被靶向蛋白水解嵌合体（PROTAC）蛋白降解物所利用，这是一类很有前途的抗癌药物。在肾细胞癌中，VHL是一个重要的肿瘤抑制因子。为了了解VHL缺失的功能后果，并确定消除VHL零细胞的靶向方法，我们在人肾上皮细胞中使用了全基因组CRISPR-Cas9筛选。我们发现，在VHL缺失时，HIF1A/ARNT复合物是细胞适应性的主要抑制剂，抑制线粒体呼吸，并且VHL缺失细胞显示出可靶向药物的HIF1A依赖分子脆弱性。乳腺癌和食管癌细胞中VHL/HIF1A联合失活也可以提供对ARV-771的抗性，ARV-771是一种基于VHL的溴结构域降解物，具有抗癌活性。因此，HIF1A的稳定可以为肿瘤性VHL克隆的早期干预提供机会，并且VHL-HIF1A轴可能与对新兴的基于protac的癌症治疗的耐药发展有关。
{"title":"Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities.","authors":"Jianfeng Ge,Shoko Hirosue,Leticia Castillon,Saroor A Patel,Ludovic Wesolowski,Anna Dyas,Cissy Yong,Sanne de Haan,Jarno Drost,Grant D Stewart,Anna C Obenauf,Daniel Muñoz-Espín,Sakari Vanharanta","doi":"10.1038/s44321-025-00361-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00361-w","url":null,"abstract":"The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"180 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785824","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}
Pub Date : 2025-12-11DOI: 10.1038/s44321-025-00353-w
Emmanouela Epeslidou,Julia S Scott,Bim de Klein,Jeremy Tan Cudia,Barbro Melgert,Stefan Prekovic
Human-driven environmental change continues to reshape global patterns of disease, as seen in past pollution-related respiratory crises. Microplastics, persistent synthetic polymer particles, have now emerged as a widespread airborne contaminant with growing relevance for lung health. Continuous inhalation exposure, particularly in indoor environments rich in synthetic fibers, raises concern about their contribution to respiratory disease. Epidemiological and experimental studies increasingly link microplastic exposure to lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, yet the underlying mechanisms remain poorly defined. This review integrates current evidence on how particle properties influence biological outcomes and outlines how different polymer types, sizes, and aging states affect lung cells through inflammation, oxidative stress, ferroptosis, epithelial-mesenchymal transition, and epigenetic change. Together, these findings suggest that microplastics may act as environmental modifiers that exacerbate disease progression. Recognizing their complex and persistent nature highlights the need for standardized exposure metrics, mechanistic research at realistic doses, and coordinated scientific and regulatory action.
{"title":"Microplastics as environmental modifiers of lung disease.","authors":"Emmanouela Epeslidou,Julia S Scott,Bim de Klein,Jeremy Tan Cudia,Barbro Melgert,Stefan Prekovic","doi":"10.1038/s44321-025-00353-w","DOIUrl":"https://doi.org/10.1038/s44321-025-00353-w","url":null,"abstract":"Human-driven environmental change continues to reshape global patterns of disease, as seen in past pollution-related respiratory crises. Microplastics, persistent synthetic polymer particles, have now emerged as a widespread airborne contaminant with growing relevance for lung health. Continuous inhalation exposure, particularly in indoor environments rich in synthetic fibers, raises concern about their contribution to respiratory disease. Epidemiological and experimental studies increasingly link microplastic exposure to lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, yet the underlying mechanisms remain poorly defined. This review integrates current evidence on how particle properties influence biological outcomes and outlines how different polymer types, sizes, and aging states affect lung cells through inflammation, oxidative stress, ferroptosis, epithelial-mesenchymal transition, and epigenetic change. Together, these findings suggest that microplastics may act as environmental modifiers that exacerbate disease progression. Recognizing their complex and persistent nature highlights the need for standardized exposure metrics, mechanistic research at realistic doses, and coordinated scientific and regulatory action.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728592","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}
Pub Date : 2025-12-11DOI: 10.1038/s44321-025-00343-y
Mark E Pepin,Xuemin Gong,Almut Schulze,Johannes Backs
Metabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations precede adverse cardiac remodeling leading to heart failure. These metabolic shifts are coupled with changes in cardiac gene expression, driven in part by chromatin-modifying enzymes, which have recently been identified as both sensors and transducers of metabolic stress and gene regulatory networks, respectively. This review synthesizes the latest evidence implicating chromatin-modifying enzymes as key regulators of metabolic reprogramming in the heart, providing a framework to understand how metabolic stressors are incorporated as epigenetic modifications that regulate cardiac gene expression. We propose a model of 'metabo-epigenetic circuitry' within which energy metabolic perturbations drive transcriptional and epigenetic changes that ultimately contribute to cardiac dysfunction. Although many nodes in these circuits remain unidentified, this viewpoint opens new avenues for investigating chromatin-modifying enzymes as therapeutic targets to halt the metabolic programs that promote heart failure.
{"title":"Metabo-epigenetic circuits of heart failure: chromatin-modifying enzymes as determinants of metabolic plasticity.","authors":"Mark E Pepin,Xuemin Gong,Almut Schulze,Johannes Backs","doi":"10.1038/s44321-025-00343-y","DOIUrl":"https://doi.org/10.1038/s44321-025-00343-y","url":null,"abstract":"Metabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations precede adverse cardiac remodeling leading to heart failure. These metabolic shifts are coupled with changes in cardiac gene expression, driven in part by chromatin-modifying enzymes, which have recently been identified as both sensors and transducers of metabolic stress and gene regulatory networks, respectively. This review synthesizes the latest evidence implicating chromatin-modifying enzymes as key regulators of metabolic reprogramming in the heart, providing a framework to understand how metabolic stressors are incorporated as epigenetic modifications that regulate cardiac gene expression. We propose a model of 'metabo-epigenetic circuitry' within which energy metabolic perturbations drive transcriptional and epigenetic changes that ultimately contribute to cardiac dysfunction. Although many nodes in these circuits remain unidentified, this viewpoint opens new avenues for investigating chromatin-modifying enzymes as therapeutic targets to halt the metabolic programs that promote heart failure.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"152 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728547","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}
Pub Date : 2025-12-09DOI: 10.1038/s44321-025-00350-z
Lennart Roos,Aida Garrido-Charles,Niels Albrecht,Anna Vavakou,Alexey Alekseev,Martina Bleyer,Anupriya Thirumalai,Artur Mittring,Theocharis Alvanos,Antoine T Huet,Ernst Bamberg,Kathrin Kusch,Bettina J Wolf,Tobias Moser,Thomas Mager
Optogenetics allows versatile control of excitable cell networks, which advances basic science research and drives the development of future medical applications. Fast-closing channelrhodopsins (ChRs) are required for high temporal fidelity of neurostimulation, but their short channel open times require sufficient plasma membrane expression and high light intensity, challenging clinical translation. Here, we addressed the need of high-rate neurostimulation by engineering optimized blue-light-sensitive ChR variants. In particular, we report on the ChR2 variant f-ChR2 TC enabling high frequency stimulation at low light requirements, due to its good plasma membrane targeted expression and balanced closing kinetics. Upon Adeno-associated virus (AAV) mediated f-ChR2 TC expression in spiral ganglion neurons of the inner ear in mice, f-ChR2 TC accordingly enabled optogenetic stimulation of the auditory nerve with sizeable responses beyond 300 Hz and low pulse energy thresholds. Translating the approach to the larger cochlea of gerbils, we tested the utility of f-ChR2 TC for evaluating multichannel optical cochlear implants with blue light emitting diodes and found light-efficient stimulation of the auditory pathway by single LEDs at rates ≥100 Hz.
{"title":"Channelrhodopsin variants for high-rate optogenetic neurostimulation at low light intensities.","authors":"Lennart Roos,Aida Garrido-Charles,Niels Albrecht,Anna Vavakou,Alexey Alekseev,Martina Bleyer,Anupriya Thirumalai,Artur Mittring,Theocharis Alvanos,Antoine T Huet,Ernst Bamberg,Kathrin Kusch,Bettina J Wolf,Tobias Moser,Thomas Mager","doi":"10.1038/s44321-025-00350-z","DOIUrl":"https://doi.org/10.1038/s44321-025-00350-z","url":null,"abstract":"Optogenetics allows versatile control of excitable cell networks, which advances basic science research and drives the development of future medical applications. Fast-closing channelrhodopsins (ChRs) are required for high temporal fidelity of neurostimulation, but their short channel open times require sufficient plasma membrane expression and high light intensity, challenging clinical translation. Here, we addressed the need of high-rate neurostimulation by engineering optimized blue-light-sensitive ChR variants. In particular, we report on the ChR2 variant f-ChR2 TC enabling high frequency stimulation at low light requirements, due to its good plasma membrane targeted expression and balanced closing kinetics. Upon Adeno-associated virus (AAV) mediated f-ChR2 TC expression in spiral ganglion neurons of the inner ear in mice, f-ChR2 TC accordingly enabled optogenetic stimulation of the auditory nerve with sizeable responses beyond 300 Hz and low pulse energy thresholds. Translating the approach to the larger cochlea of gerbils, we tested the utility of f-ChR2 TC for evaluating multichannel optical cochlear implants with blue light emitting diodes and found light-efficient stimulation of the auditory pathway by single LEDs at rates ≥100 Hz.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710901","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}
Pub Date : 2025-12-09DOI: 10.1038/s44321-025-00357-6
Suresh Chava,Suresh Bugide,Parmanand Malvi,Kelly D DeMarco,Boyang Ma,Chaitanya N Parikh,Marcus Ruscetti,Allan Zajac,Guoping Cai,Romi Gupta,Narendra Wajapeyee
Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 as a key suppressor of NK cell-mediated cytotoxicity. EHMT2 inhibition in cancer cells enhanced NK cell-mediated elimination of diverse cancers, including uveal melanoma, breast cancer, and pancreatic cancer. EHMT2 loss increased AZGP1 and decreased TGF-β1 levels, resulting in the autocrine elevation of NKG2D ligands MICB and ULBP3, chemokines in cancer cells, and the paracrine stimulation of NK cell function. In a syngeneic pancreatic cancer model, EHMT2 inhibition suppressed tumors in an NK cell-dependent manner, as NK cell depletion restored tumor growth. This effect persisted and remained dependent on NK cells in Rag2 knockout mice (lacking T and B cells), but not in NSG mice (lacking T-, B- and NK-cells). Furthermore, EHMT2 and TGF-β1 inhibitors suppressed tumors in immunocompetent, but not in immunodeficient mice. These findings establish EHMT2 as a suppressor of NK cell-mediated anti-tumor immunity and a promising therapeutic target.
{"title":"Loss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression.","authors":"Suresh Chava,Suresh Bugide,Parmanand Malvi,Kelly D DeMarco,Boyang Ma,Chaitanya N Parikh,Marcus Ruscetti,Allan Zajac,Guoping Cai,Romi Gupta,Narendra Wajapeyee","doi":"10.1038/s44321-025-00357-6","DOIUrl":"https://doi.org/10.1038/s44321-025-00357-6","url":null,"abstract":"Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 as a key suppressor of NK cell-mediated cytotoxicity. EHMT2 inhibition in cancer cells enhanced NK cell-mediated elimination of diverse cancers, including uveal melanoma, breast cancer, and pancreatic cancer. EHMT2 loss increased AZGP1 and decreased TGF-β1 levels, resulting in the autocrine elevation of NKG2D ligands MICB and ULBP3, chemokines in cancer cells, and the paracrine stimulation of NK cell function. In a syngeneic pancreatic cancer model, EHMT2 inhibition suppressed tumors in an NK cell-dependent manner, as NK cell depletion restored tumor growth. This effect persisted and remained dependent on NK cells in Rag2 knockout mice (lacking T and B cells), but not in NSG mice (lacking T-, B- and NK-cells). Furthermore, EHMT2 and TGF-β1 inhibitors suppressed tumors in immunocompetent, but not in immunodeficient mice. These findings establish EHMT2 as a suppressor of NK cell-mediated anti-tumor immunity and a promising therapeutic target.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710900","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}
Relapse in melanoma after targeted or immune therapy necessitates the rapid identification of effective alternatives. To address this gap, we investigated whether the timely generation of preclinical models for functional drug testing could reveal additional therapeutic options. Our study focused on: (i) the feasibility of generating in vivo and in vitro models from melanoma lymph node (LN)-derived disseminated cancer cells (DCCs) before relapse, (ii) the implementation of preclinical models to identify therapeutic alternatives, and (iii) the ability to detect patients who could benefit from early functional in vitro drug testing. Successful model generation was significantly associated with DCC quantity, LN origin, and mortality risk. All patient-derived xenograft models were available before patient death and, in 82% of cases, before relapse. Proof-of-concept in vitro drug screening using 315 anti-cancer drugs identified additional candidates, and coculture of DCCs and LN cells revealed specific T-cell activation and responses to immunotherapy. Our data establish a process for selecting melanoma patients at high risk of progression, enabling the timely generation of patient-derived models to support functionally guided treatment decisions at relapse.
{"title":"Micrometastasis-derived models enable drug testing for early-stage, high-risk melanoma patients.","authors":"Kathrin Weidele,Christian Werno,Steffi Treitschke,Catherine Botteron,Martin Hoffmann,Sebastian Scheitler,Lukas Wöhrl,Zbigniew Czyz,Giancarlo Feliciello,Florian Weber,Adithi Ravikumar Varadarajan,Jens Warfsmann,Silvia Materna-Reichelt,Marie Katzer,Laura Schreieder,Parvaneh Mohammadi,Hedayatollah Hosseini,Kamran Honarnejad,Sebastian Haferkamp,Melanie Werner-Klein,Christoph A Klein","doi":"10.1038/s44321-025-00339-8","DOIUrl":"https://doi.org/10.1038/s44321-025-00339-8","url":null,"abstract":"Relapse in melanoma after targeted or immune therapy necessitates the rapid identification of effective alternatives. To address this gap, we investigated whether the timely generation of preclinical models for functional drug testing could reveal additional therapeutic options. Our study focused on: (i) the feasibility of generating in vivo and in vitro models from melanoma lymph node (LN)-derived disseminated cancer cells (DCCs) before relapse, (ii) the implementation of preclinical models to identify therapeutic alternatives, and (iii) the ability to detect patients who could benefit from early functional in vitro drug testing. Successful model generation was significantly associated with DCC quantity, LN origin, and mortality risk. All patient-derived xenograft models were available before patient death and, in 82% of cases, before relapse. Proof-of-concept in vitro drug screening using 315 anti-cancer drugs identified additional candidates, and coculture of DCCs and LN cells revealed specific T-cell activation and responses to immunotherapy. Our data establish a process for selecting melanoma patients at high risk of progression, enabling the timely generation of patient-derived models to support functionally guided treatment decisions at relapse.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"7 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680609","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}
Pub Date : 2025-12-01Epub Date: 2025-11-10DOI: 10.1038/s44321-025-00333-0
Silei Sui, Yuan Li, Joan Maurel, Ajay Goel
Cetuximab, an EGFR-targeting monoclonal antibody, provides beneficial yet limited clinical improvement in KRAS wild-type metastatic colorectal cancer (mCRC). While circRNA dysregulation has been implicated in various cancers, the role of circ-EGFR in response to EGFR-targeted therapy in mCRC remains largely unexplored. Here, we identified circ-EGFR as a promising predictive biomarker for cetuximab response. Clinically, we first determined that tissue-based circ-EGFR biomarker effectively stratified responders from non-responders to cetuximab in mCRC, with an Area under the Curve (AUC) of 76.8%. Functional assays demonstrated that circ-EGFR enhances the sensitivity to cetuximab, whereas its depletion induces resistance in CRC. Mechanistically, we revealed that circ-EGFR functions as a sponge for miR-942-3p, resulting in the upregulation of GAS1, which activates the Hedgehog signaling pathway and promotes the efficacy of cetuximab in CRC. Importantly, we effectively translated this tissue-based biomarker into a liquid biopsy predictor for anti-EGFR response (AUC: 76.9%), highlighting its non-invasive potential. In conclusion, circ-EGFR is a significant predictor of cetuximab efficacy in mCRC, potentially aiding in patient selection and treatment management, especially for patients with low circ-EGFR expression.
{"title":"circ-EGFR is a predictor of response to Cetuximab and a potential target in colorectal cancer.","authors":"Silei Sui, Yuan Li, Joan Maurel, Ajay Goel","doi":"10.1038/s44321-025-00333-0","DOIUrl":"10.1038/s44321-025-00333-0","url":null,"abstract":"<p><p>Cetuximab, an EGFR-targeting monoclonal antibody, provides beneficial yet limited clinical improvement in KRAS wild-type metastatic colorectal cancer (mCRC). While circRNA dysregulation has been implicated in various cancers, the role of circ-EGFR in response to EGFR-targeted therapy in mCRC remains largely unexplored. Here, we identified circ-EGFR as a promising predictive biomarker for cetuximab response. Clinically, we first determined that tissue-based circ-EGFR biomarker effectively stratified responders from non-responders to cetuximab in mCRC, with an Area under the Curve (AUC) of 76.8%. Functional assays demonstrated that circ-EGFR enhances the sensitivity to cetuximab, whereas its depletion induces resistance in CRC. Mechanistically, we revealed that circ-EGFR functions as a sponge for miR-942-3p, resulting in the upregulation of GAS1, which activates the Hedgehog signaling pathway and promotes the efficacy of cetuximab in CRC. Importantly, we effectively translated this tissue-based biomarker into a liquid biopsy predictor for anti-EGFR response (AUC: 76.9%), highlighting its non-invasive potential. In conclusion, circ-EGFR is a significant predictor of cetuximab efficacy in mCRC, potentially aiding in patient selection and treatment management, especially for patients with low circ-EGFR expression.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3525-3554"},"PeriodicalIF":8.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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