Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-13DOI: 10.1016/j.xcrm.2025.102192
Sarah Naomi Olsen, Bryn Anderson, Charlie Hatton, Zhengtao Chu, Christopher Simpkins, Yanhe Wen, Wallace Bourgeois, Elena L Haarer, Myles Brown, Rinath Jeselsohn, Alana L Welm, Eneda Toska, Scott A Armstrong
{"title":"Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer.","authors":"Sarah Naomi Olsen, Bryn Anderson, Charlie Hatton, Zhengtao Chu, Christopher Simpkins, Yanhe Wen, Wallace Bourgeois, Elena L Haarer, Myles Brown, Rinath Jeselsohn, Alana L Welm, Eneda Toska, Scott A Armstrong","doi":"10.1016/j.xcrm.2025.102192","DOIUrl":"10.1016/j.xcrm.2025.102192","url":null,"abstract":"<p><p>KAT6A is a histone acetyltransferase that is emerging as a therapeutic target in cancer, including estrogen receptor-positive (ER+) breast cancer. Here, we perform CRISPR screens to identify the chromatin adaptor Menin as a regulator of KAT6A/B inhibitor response. Co-treatment with KAT6A/B and Menin inhibitors has synergistic anti-proliferative effects in ER+, but not ER-, breast cancer lines. Our data reveal that KAT6A and Menin-KMT2A cooperatively regulate ER-driven gene expression via direct effects on ESR1 expression and co-localization at ER target genes. Combined KAT6A/B and Menin inhibition displaces KAT6A and Menin-KMT2A from promoters of ER-driven genes leading to selective RNA polymerase II chromatin loss at these loci. Importantly, combined KAT6A/B and Menin inhibition is effective in ER+ patient-derived xenograft models and in multiple models of endocrine resistance. KAT6A/B and Menin inhibitors are currently in clinical trials and have shown manageable toxicity profiles, underscoring the potential therapeutic relevance for ER+ breast cancer.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102192"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293404","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":"CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma.","authors":"Minghao Xu, Yimin Zheng, Junbo Chen, Chao Gao, Miao Zhu, Aying Ma, Bugang Liang, Wenxin Xu, Jia Fan, Haibo Zhou, Aiwu Ke, Yinghao Shen","doi":"10.1016/j.xcrm.2025.102208","DOIUrl":"10.1016/j.xcrm.2025.102208","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) exhibits significant plasticity, enabling phenotypic switching that promotes a drug-tolerant state and circumvents drug-induced cytotoxicity. In this study, we identify the hepatic-to-biliary lineage transition (HBT), associated with Claudin 4 (CLDN4), a tight junction protein, as a potential target for mitigating lenvatinib resistance in HCC. CLDN4 expression is more prevalent in lenvatinib-resistant patients. Palmitoylation of CLDN4 at cysteine residues C104 and C107 regulates ubiquitination at lysine residue K103, inhibits clathrin-mediated endocytosis, and sustains CLDN4 anchoring within lipid rafts. Anchored CLDN4 facilitates the phenotypic transition of HCC cells, resulting in increased resistance to lenvatinib by driving the mobilization of contactin-1 to lipid rafts and activating the Notch signaling pathway. Salvianolic acid B, an inhibitor of CLDN4, is demonstrated to reduce both HBT and lenvatinib resistance in HCC. Additionally, combination chemotherapy appears to be an effective therapeutic strategy for HCC patients undergoing HBT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102208"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539146","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":"AI-enabled molecular phenotyping and prognostic predictions in lung cancer through multimodal clinical information integration.","authors":"Yuxing Lu, Fei Liu, Yunfang Yu, Bojiang Chen, Wenyao Yu, Zixing Zou, Kun Li, Miao Man, Caiwen Ou, Chengdi Wang, Kang Zhang, Jinzhuo Wang, Xiaoying Huang","doi":"10.1016/j.xcrm.2025.102216","DOIUrl":"10.1016/j.xcrm.2025.102216","url":null,"abstract":"<p><p>Lung cancer remains the leading cause of cancer-related mortality worldwide. The need for cost-effective, non-invasive methods to detect specific gene mutations for targeted therapy and predict patient survival outcomes underscores the importance of advancing diagnostic and prognostic capabilities. Contemporary lung cancer diagnostic models often fail to integrate diverse patient data, leading to incomplete clinical assessments. To address these challenges, we propose LUCID, a multimodal data integration framework designed to predict epidermal growth factor receptor (EGFR) mutation status and survival outcomes in patients with lung cancer. Tailored for early-stage clinical assessment, LUCID leverages lung computed tomography (CT) images, chief complaints, laboratory test results, and demographic data to deliver comprehensive, non-invasive predictions. LUCID achieved strong performance in a retrospective cohort of 5,175 patients, with areas under the receiver operating characteristic curve (AUCs) ranging from 0.851 to 0.881 for EGFR mutation prediction and from 0.821 to 0.912 for survival time prediction. The model also demonstrated robustness across external validation cohorts and in scenarios with missing modalities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102216"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559341","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}
Lina Omary, Emanuel E Canfora, Marie-Luise Puhlmann, Asimenia Gavriilidou, Iris Rijnaarts, Jens J Holst, Yvonne M H Op den Kamp-Bruls, Willem M de Vos, Ellen E Blaak
{"title":"Intrinsic chicory root fibers modulate colonic microbial butyrate-producing pathways and improve insulin sensitivity in individuals with obesity.","authors":"Lina Omary, Emanuel E Canfora, Marie-Luise Puhlmann, Asimenia Gavriilidou, Iris Rijnaarts, Jens J Holst, Yvonne M H Op den Kamp-Bruls, Willem M de Vos, Ellen E Blaak","doi":"10.1016/j.xcrm.2025.102237","DOIUrl":"10.1016/j.xcrm.2025.102237","url":null,"abstract":"<p><p>Type 2 diabetes and obesity have become major public health concerns. Growing evidence suggests that increased dietary fiber intake, through its interaction with the gut microbiota, may help prevent these diseases. Here, we demonstrate in a 12-week randomized, placebo-controlled trial in individuals at risk for type 2 diabetes that intake of an intrinsic fiber product, consisting of entire plant cells, tended to improve peripheral insulin sensitivity (p = 0.085), increased whole-body insulin sensitivity (p = 0.032), reduced circulating triglycerides (p = 0.049), and tended to reduce intrahepatic lipid content (p = 0.063), along with an increased proportion of small adipocytes (p = 0.008). Phylogenetic and metagenomic analysis revealed that these outcomes coincided with increased levels of fiber-degrading Bifidobacterium spp. and butyrate-producing Anaerostipes spp. and a functional shift toward a distal butyrogenic trophic chain while the best responding individuals had increased levels of pectin degraders that may produce propionate. Our findings demonstrate the pivotal role of slowly fermented, intrinsic plant cell fibers in improving cardiometabolic health. This study was registered at ClinicalTrials.gov (NCT04714944).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 7","pages":"102237"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648701","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-06DOI: 10.1016/j.xcrm.2025.102161
Taylon F Silva, Elizabeth Hutchins, Wenyan Zhao, Yari Ciani, Minhyung Kim, Emily Ko, Javier Mariscal, Zhuyu Qiu, Fatima Bedier, Agnes Kittel, Bo Zhou, Yang Wang, Megan Hall, Francesca Galasso, Rebecca Reiman, Michael R Freeman, Sarah Parker, Jennifer Van Eyk, Wei Yang, Edwin Posadas, Jlenia Guarnerio, John Nolan, Clotilde Théry, Andries Zijlstra, Shannon Stott, Sungyong You, Francesca Demichelis, Paul C Boutros, Kendall Van Keuren-Jensen, Dolores Di Vizio
{"title":"Extracellular vesicle heterogeneity through the lens of multiomics.","authors":"Taylon F Silva, Elizabeth Hutchins, Wenyan Zhao, Yari Ciani, Minhyung Kim, Emily Ko, Javier Mariscal, Zhuyu Qiu, Fatima Bedier, Agnes Kittel, Bo Zhou, Yang Wang, Megan Hall, Francesca Galasso, Rebecca Reiman, Michael R Freeman, Sarah Parker, Jennifer Van Eyk, Wei Yang, Edwin Posadas, Jlenia Guarnerio, John Nolan, Clotilde Théry, Andries Zijlstra, Shannon Stott, Sungyong You, Francesca Demichelis, Paul C Boutros, Kendall Van Keuren-Jensen, Dolores Di Vizio","doi":"10.1016/j.xcrm.2025.102161","DOIUrl":"10.1016/j.xcrm.2025.102161","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are heterogeneous in size, biogenesis, content, and function. Aggressive cancer cells release a distinct, poorly characterized, and particularly large EV subtype, namely large oncosomes (LOs). This study employs an optimized method to improve LO yields and integrates mass spectrometry and RNA sequencing (RNA-seq) to profile their molecular cargo. A consistent set of proteins enriched in LOs is identified across glioma, prostate, and breast cancer cell lines. These proteins are also present as mRNA in LOs from the prostate cancer model and are abundant in plasma LOs from 20 patients with metastasis. Single-LO RNA-seq confirms bulk LO cargo, demonstrating the utility of single-cell technologies for large vesicle analysis. Our patient study provides proof-of-principle evidence that we can use multiomics to delve into EV heterogeneity, biogenesis, and composition. It also suggests that plasma LOs help stratify patients, supporting their potential prognostic value for developing a multi-analyte approach for liquid biopsy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102161"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246604","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-20DOI: 10.1016/j.xcrm.2025.102194
Raúl Del Rey-Vergara, Miguel Alejandro Galindo-Campos, Pedro Rocha, Marina Carpes, Carlos Martínez, Laura Masfarré, Silvia Menéndez, Fabricio Quimis, Adrià Rossell, Albert Iñañez, Sandra Pérez-Buira, Federico Rojo, Ramon Gimeno, Dolores Isla, Jon Zugazagoitia, Cristina Martí Blanco, Rosario García-Campelo, Alberto Moreno-Vega, Luis León-Mateos, Ángel Callejo Mellén, Kwon-Sik Park, Simon Heeke, John V Heymach, Álvaro Taus, Luis Paz-Ares, Ana Rovira, Edurne Arriola
{"title":"MET pathway inhibition increases chemo-immunotherapy efficacy in small cell lung cancer.","authors":"Raúl Del Rey-Vergara, Miguel Alejandro Galindo-Campos, Pedro Rocha, Marina Carpes, Carlos Martínez, Laura Masfarré, Silvia Menéndez, Fabricio Quimis, Adrià Rossell, Albert Iñañez, Sandra Pérez-Buira, Federico Rojo, Ramon Gimeno, Dolores Isla, Jon Zugazagoitia, Cristina Martí Blanco, Rosario García-Campelo, Alberto Moreno-Vega, Luis León-Mateos, Ángel Callejo Mellén, Kwon-Sik Park, Simon Heeke, John V Heymach, Álvaro Taus, Luis Paz-Ares, Ana Rovira, Edurne Arriola","doi":"10.1016/j.xcrm.2025.102194","DOIUrl":"10.1016/j.xcrm.2025.102194","url":null,"abstract":"<p><p>The introduction of immunotherapy as a first-line treatment for advanced small cell lung cancer (SCLC) represents significant progress, yet there remains an opportunity to further improve patient outcomes. Hepatocyte growth factor (HGF) receptor (MET) pathway activation promotes epithelial-mesenchymal transition, driving chemoresistance and potentially impairing the efficacy of immunotherapy. In SCLC mouse models, adding MET inhibition to chemo-immunotherapy (anti-PD-L1) reduces tumor growth, extends survival, and reshapes the tumor microenvironment by decreasing suppressive myeloid cell infiltration and enhancing the immune response. Analysis of pretreatment human SCLC tumor samples reveals that myeloid-enriched immune infiltrates may contribute to chemo-immunotherapy resistance. Elevated serum HGF levels are associated with a mesenchymal and inflamed phenotype, suggesting that patients with these characteristics might benefit from MET inhibitor-based therapeutic strategies. These findings provide strong preclinical and translational evidence supporting MET inhibition as a therapeutic approach to overcome treatment resistance, enhancing the immune response and improving outcomes in biomarker-defined subsets of SCLC patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102194"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339947","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":"Metabolic fingerprinting enables rapid, label-free histopathology in gastric cancer diagnosis and prognostic prediction.","authors":"Fei Teng, Juxiang Zhang, Yida Huang, Wei Xu, Wanshan Liu, Liming Sun, Meng Yan, Jiao Wu, Ruimin Wang, Shouzhi Yang, Lin Huang, Zhengying Gu, Haiyang Su, Xiaoyu Xu, Dingyitai Liang, Ning Ren, Chunmeng Ding, Yanyan Li, Qiongzhu Dong, Lingchuan Guo, Shaoqun Liu, Xuefei Wang, Kun Qian","doi":"10.1016/j.xcrm.2025.102238","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102238","url":null,"abstract":"<p><p>Histopathological evaluation is a cornerstone of cancer identification but often involves time-consuming labeling processes (∼days per sample) and experience-dependent interpretation. Herein, we introduce a rapid (∼40 min per sample) and label-free histopathological method based on metabolic fingerprinting of tissue using nanoparticle-enhanced laser desorption/ionization mass spectrometry. Applied to gastric cancer (GC, n = 284 paired tissue), this approach distinguishes malignant from benign tissues (area under the curve [AUC] of 0.979), identifies tumor subtypes (AUC of 0.963), and assesses prognosis (p < 0.05) without specialized pathologists. External validation on 238 samples from an independent cohort confirmed its robustness. This method advances histopathological analysis, offering potential for scalable clinical use.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 7","pages":"102238"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648702","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":"Ce6 derivative photodynamic therapy triggers PANoptosis and enhances antitumor immunity with LAG3 blockade in cutaneous squamous cell carcinoma.","authors":"Diyan Chen, Bo Wang, Chunying Li, Hui Tao, Fangqi Lu, Zhijie Ruan, Zijun Zhao, Chunxiao Li, Guorong Yan, Haiyan Zhang, Yeqiang Liu, Xiuli Wang, Guolong Zhang, Qingyu Zeng","doi":"10.1016/j.xcrm.2025.102239","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102239","url":null,"abstract":"<p><p>Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of nonmelanoma skin cancer, with 2.4 million cases annually and significant mortality. Photodynamic therapy (PDT) is a promising antitumor strategy, and its integration with immunotherapy has garnered attention. Herein, we develop STBF, a modified chlorin e6 derivative with superior solubility and efficacy, and propose a treatment paradigm integrating PDT with immunotherapy to address conventional PDT limitations in advanced cSCC. Mechanically, STBF-PDT induces PANoptosis, triggering immunogenic cell death through the stimulator of interferon genes (STING) pathway, while the STING agonist amplifies these effects and promotes dendritic cell activation. STBF-PDT reshapes the tumor microenvironment, enhancing immune checkpoint inhibitor responses. Incorporating lymphocyte activation gene 3 (LAG3) blockade further strengthens systemic antitumor immunity by suppressing myeloid-derived suppressor cells while augmenting type 2 conventional dendritic cells, cytotoxic T lymphocytes, and tissue-resident memory T cells. Our findings highlight the potential of STBF-PDT-STING agonism-anti-LAG3 combinations for metastatic and locally advanced cSCC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 7","pages":"102239"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648699","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}
Kolja Siebert, Tim Faro, Nikolai Köhler, Hannes Hölz, Sebastian Jarosch, Monica Matchado, Deborah Häcker, Federica De Zen, Mohammad Samer Hajji, Eberhard Lurz, Sibylle Koletzko, Josch K Pauling, Katja Steiger, Klaus Neuhaus, Caspar Ohnmacht, Markus List, Dirk H Busch, Dirk Haller, Tobias Schwerd
{"title":"Endoscopic healing in pediatric IBD perpetuates a persistent signature defined by Th17 cells with molecular and microbial drivers of disease.","authors":"Kolja Siebert, Tim Faro, Nikolai Köhler, Hannes Hölz, Sebastian Jarosch, Monica Matchado, Deborah Häcker, Federica De Zen, Mohammad Samer Hajji, Eberhard Lurz, Sibylle Koletzko, Josch K Pauling, Katja Steiger, Klaus Neuhaus, Caspar Ohnmacht, Markus List, Dirk H Busch, Dirk Haller, Tobias Schwerd","doi":"10.1016/j.xcrm.2025.102236","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102236","url":null,"abstract":"<p><p>Endoscopic healing (EH) is the major long-term treatment target for inflammatory bowel diseases (IBDs), mainly achieved by immune-suppressive therapies. However, the chronic and relapsing nature of the disease indicates a lifelong persistence of unknown tissue-associated IBD residues. Based on longitudinally collected gastrointestinal biopsies (n = 217) from pediatric patients with IBD (N = 32) and pediatric non-IBD controls (N = 5), we describe cellular, molecular, and microbial drivers of IBD that persist under EH in the terminal ileum and sigmoid colon. Whole biopsy transcriptomics in combination with single T cell analysis (72,026 cells) characterizes an inflammatory bowel residual disease (IBrD) signature, connecting stress- and inflammation-related tissue markers (e.g., DUOX2, SAA2, and NOS2) with pathogenic interleukin-17 (IL-17)-producing T helper cells. 16S rRNA gene sequencing reveals individual microbial composition with persistently low diversity, irrespective of disease location and activity. Overall, our study identifies a persisting IBD signature that reflects ongoing mucosal alterations despite EH. These markers may provide targets for future or sequential therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 7","pages":"102236"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648700","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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