Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter
{"title":"A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.","authors":"Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter","doi":"10.1016/j.xcrm.2026.102770","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102770","url":null,"abstract":"<p><p>Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102770"},"PeriodicalIF":10.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763813","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}
Jonathan H Sussman, Derek A Oldridge, Wenbao Yu, Chia-Hui Chen, Abigail M Zellmer, Jiazhen Rong, Arianne Parvaresh-Rizi, Anusha Thadi, Austin Yang, Joseph S Tumulty, Barbara Xiong, David W Wu, Yusha Sun, Shovik Bandyopadhyay, Jason Xu, Stephanie Brosius, Una Yamamoto Barkardottir, Isabelle Seka, Kyung Jin Ahn, Omar Elghawy, Amy E Baxter, Mateusz P Koptyra, Rami S Vanguri, Stephanie McGrory, Phillip B Storm, Nduka M Amankulor, Mariarita Santi, Angela N Viaene, Nancy Zhang, Thomas De Raedt, Kristina Cole, Kai Tan
{"title":"A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.","authors":"Jonathan H Sussman, Derek A Oldridge, Wenbao Yu, Chia-Hui Chen, Abigail M Zellmer, Jiazhen Rong, Arianne Parvaresh-Rizi, Anusha Thadi, Austin Yang, Joseph S Tumulty, Barbara Xiong, David W Wu, Yusha Sun, Shovik Bandyopadhyay, Jason Xu, Stephanie Brosius, Una Yamamoto Barkardottir, Isabelle Seka, Kyung Jin Ahn, Omar Elghawy, Amy E Baxter, Mateusz P Koptyra, Rami S Vanguri, Stephanie McGrory, Phillip B Storm, Nduka M Amankulor, Mariarita Santi, Angela N Viaene, Nancy Zhang, Thomas De Raedt, Kristina Cole, Kai Tan","doi":"10.1016/j.xcrm.2026.102766","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102766","url":null,"abstract":"<p><p>Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities with adult glioma, it comprises distinct disease entities. In this study, we longitudinally profile a molecularly diverse cohort of 16 pHGG patients through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of neoplastic and microenvironmental features during disease progression and treatment. We define a set of core pHGG neoplastic cell states and observe differential tumor-myeloid interactions between malignant cell phenotypes. We find that essential neuromodulators and the interferon response are upregulated post-therapy, implicating them as malignant cell-intrinsic targets. We observe an increase in oligodendrocytes upon progression and that they coordinate spatial motifs with proneural tumor cells. This multiomic atlas of longitudinal pHGG captures features of therapy response and provides a scalable reference for the study of pediatric brain tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102766"},"PeriodicalIF":10.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763757","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}
Jie Liu, Mei Li, Jianming Huang, Yujie Xia, Guanfeng Jiang, Hong'an Zhang, Jiaxin Yang, Mingfeng Jiang, Yalan Liu, Yilun Luo, Liefeng Wang, Shuyong Zhang
{"title":"Overcoming ADC resistance in advanced colorectal cancer by dual targeting of TROP2 and PERK to suppress Wnt/β-catenin signaling.","authors":"Jie Liu, Mei Li, Jianming Huang, Yujie Xia, Guanfeng Jiang, Hong'an Zhang, Jiaxin Yang, Mingfeng Jiang, Yalan Liu, Yilun Luo, Liefeng Wang, Shuyong Zhang","doi":"10.1016/j.xcrm.2026.102769","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102769","url":null,"abstract":"<p><p>Targeted therapy for advanced colorectal cancer (CRC) remains a significant unmet clinical need. Here, we investigate the mechanism of the anti-TROP2 antibody-drug conjugate IMMU132, delivering SN-38 to induce TOP1-mediated DNA damage and cytotoxicity. We further discover that it concurrently suppresses the PERK-eIF2α-ATF4 axis of the unfolded protein response, a key adaptive survival pathway activated by therapy-induced endoplasmic reticulum (ER) stress. This dual action of direct killing and stress adaptation disruption may dismantle a key resistance mechanism. Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102769"},"PeriodicalIF":10.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763768","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}
Fu-Hui Xiao, Hao-Tian Wang, Long Zhao, Gong-Hua Li, Si-Yu Ma, Li-Qin Yang, Hua Wang, Yun-Xia Zhang, Ji Li, Qing-Peng Kong
{"title":"Preserved mitochondrial ribosomal protein gene expression marks a youthful transcriptional state in Chinese nonagenarians and centenarians.","authors":"Fu-Hui Xiao, Hao-Tian Wang, Long Zhao, Gong-Hua Li, Si-Yu Ma, Li-Qin Yang, Hua Wang, Yun-Xia Zhang, Ji Li, Qing-Peng Kong","doi":"10.1016/j.xcrm.2026.102767","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102767","url":null,"abstract":"<p><p>A youthful molecular profile reflects attenuated aging and preserved health in advanced age. Long-lived individuals (LLIs) show youthful patterns in DNA methylation and gut microbiota, yet their transcriptional trajectories remain undercharacterized. We analyze transcriptomes from 811 LLIs and 940 younger controls (YCs) to map transcriptional aging trajectories. Clocks trained on YCs reveal that LLIs possess markedly younger transcriptional ages than expected. We identify gene clusters deviating from YC-derived aging trajectories in LLIs, notably eight mitochondrial ribosomal protein genes (mRPGs) resisting typical age-related expression decline. An elevated 8-mRPG expression score correlates with lower aging levels inferred from established aging- and senescence-related gene gets. Samples with higher 8-mRPG scores exhibit increased expression of mitochondrial-function-related genes, including those in aerobic respiration and respiratory electron transport. Together, these findings indicate that the sustained expression of specific mRPGs in LLIs is a signature of attenuated transcriptomic aging that may reflect preserved mitochondrial function.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102767"},"PeriodicalIF":10.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763836","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":"Intracellular sclerostin promotes tumor progression and metastasis as a potential therapeutic target in triple-negative breast cancer.","authors":"Meiheng Sun, Hang Luo, Shuangying Qiao, Zefeng Chen, Hewen Jiang, Xin Yang, Shijian Ding, Yuan Tian, Yingchao Wu, Peng Wu, Yihao Zhang, Xiaohui Tao, Yuanyuan Yu, Luyao Wang, Jianhui Tian, Wei Kang, Daqing Ma, Yixin He, Aiping Lu, Feng-Lai Yuan, Yuan Ma, Fangfei Li, Bao-Ting Zhang, Qianjun Chen, Ge Zhang","doi":"10.1016/j.xcrm.2026.102763","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102763","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) urgently requires promising therapeutic targets. This study identifies sclerostin, an osteocyte-derived secretory protein traditionally linked to bone homeostasis, as an unexpected intracellular oncogenic driver in TNBC. Although genetic ablation of sclerostin markedly suppresses tumor progression and lung metastasis, neither its antibody nor recombinant protein exerts any effects, excluding the role of extracellular sclerostin in TNBC. Genetic and pharmacological approaches (sclerostin aptamer-based proteolysis-targeting chimera with potent intracellular sclerostin-degrading activity, Apc101) show the emerging role of intracellular sclerostin in promoting TNBC progression and metastasis. Notably, in both TNBC cell-derived and patient-derived xenograft models, Apc101 significantly suppresses tumor progression. Mechanistically, intracellular sclerostin interacts with caprin1 to stabilize CDK1 and Cyclin B1 mRNAs. Collectively, this study reveals an oncogenic function of intracellular sclerostin in TNBC and proposes that targeting it represents a promising therapeutic strategy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102763"},"PeriodicalIF":10.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763828","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":"Nano-granulated zoledronate sensitizes innate immune metabolism to enhance vaccine-induced and antitumor immunity.","authors":"Meifang Chen, Xiaojia Jiao, Zhicheng Yan, Yueheng Wang, Jing Zhang, Qinghua Wu, Minghui Li, Shumin Fan, Yuan Wang, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang, Bing He","doi":"10.1016/j.xcrm.2026.102765","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102765","url":null,"abstract":"<p><p>Metabolic reprogramming targeting the mevalonate pathway represents an emerging innate immune activation target. However, its regulatory mechanisms remain incompletely elucidated. Here, we target the mevalonate pathway and construct a nano-granulated zoledronate (Nano-ZD) modulator. Following subcutaneous injection, Nano-ZD preferentially accumulates in draining lymph nodes rather than in bone tissues, enabling targeted delivery to innate immune cells. Nano-ZD functions as an immune-metabolic adjuvant, sensitizing and amplifying immune responses. By integrating Nano-ZD with the TLR4 agonist monophosphoryl lipid A (MPLA), MPLA-loaded Nano-ZD (Nano-ZDM) elicits robust humoral and antitumor cellular immunity. Mechanistically, Nano-ZD not only inhibits the isoprenylation of RhoA GTPases but also reduces coenzyme Q (CoQ) biosynthesis. CoQ deficiency disrupts oxidative phosphorylation (OXPHOS) and pyrimidine metabolism, causes mitochondrial ROS accumulation, induces mitochondrial antiviral protein (MAVS) oligomerization, and activates the pyrin inflammasome. This mevalonate-CoQ-OXPHOS/pyrimidine metabolism axis serves as a promising target for screening additional immune-metabolic adjuvants, and nanofabrication offers a paradigm for the lymph-targeted in vivo delivery of such adjuvants.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102765"},"PeriodicalIF":10.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763842","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":"AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.","authors":"Keisuke Kitakaze, Yukiya Ohnishi, Daisuke Tsuji, Ryosuke Watanabe, Nijiho Kamori, Yuko Katakai, Hiroaki Shibata, Sota Yoshizawa, Mika Ito, Naomi Takino, Shin-Ichi Muramatsu, Kohji Itoh","doi":"10.1016/j.xcrm.2026.102762","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.102762","url":null,"abstract":"<p><p>GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are substituted from HEXA. The intracerebroventricular administration of AAV9/3-modHEXB in SD mice results in modHexB expression in the brain, reduces GM2 accumulation, and attenuates neuroinflammation. Furthermore, AAV9/3-modHEXB rescues motor function, and longer lifespan in SD mice. In addition, intrathecal administration in non-human primates and rats demonstrates broad biodistribution and an overall favorable safety profile. These findings support the translational potential of AAV9/3-modHEXB as a gene therapy approach for TSD and SD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102762"},"PeriodicalIF":10.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763754","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":"Combination immunotherapy for colorectal cancer: Clinical applications, rationale, challenges, and future perspectives.","authors":"Jiang Fei, Changjing Cai, Wantao Wu, Hong Shen, Ying Han, Shan Zeng","doi":"10.1016/j.xcrm.2026.102728","DOIUrl":"10.1016/j.xcrm.2026.102728","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Although immunotherapy has demonstrated remarkable efficacy in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, most proficient mismatch repair (pMMR)/microsatellite stability (MSS)/microsatellite instability-low (MSI-L) patients derive limited benefit. Combination strategies-including immune checkpoint inhibitors (ICIs), chemotherapy, targeted therapy, and radiotherapy-offer promise for overcoming resistance. This review examines recent clinical advances in combination immunotherapy for CRC, with a focus on tumor microenvironment (TME) modulation and predictive biomarkers. By bridging preclinical insights and clinical applications, we aim to facilitate the optimization of therapeutic strategies and extend the benefits of immunotherapy across CRC subtypes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102728"},"PeriodicalIF":10.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637491","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}
{"title":"Engineered oncolytic virus armed with anti-PCSK9 scFv boosts long-term CD8<sup>+</sup> T cell immunity via rewiring MHC-I antigen presentation.","authors":"Huolun Feng, Yuhan Zhang, Zuda Huang, Jianlong Zhou, Yongfeng Liu, Xiao Xiao, Mingxi Chen, Xin Guo, Jiabin Zheng, Zejian Lyu, Weixian Hu, Deqing Wu, Yong Li, Fan Xing","doi":"10.1016/j.xcrm.2026.102724","DOIUrl":"10.1016/j.xcrm.2026.102724","url":null,"abstract":"<p><p>Oncolytic viruses (OVs) are widely studied for their ability to lyse cancer cells and prime immune responses; however, the immune consequences triggered by OVs remain incompletely understood. Here, we discover that oncolytic VSVΔ51 treatment suppresses the T cell receptor signaling of tumor-infiltrating T cells. Mechanistically, VSVΔ51-infected cancer cells upregulate PCSK9 secretion, which triggers lysosomal degradation of major histocompatibility complex (MHC)-I in bystander cells. PCSK9 inhibition synergizes with VSVΔ51 treatment to suppress tumor growth in multiple colorectal cancer models and induce complete regression in a microsatellite-stable (MSS) tumor model. This combination fosters stem-like CD8<sup>+</sup> T cells and establishes anti-tumor memory. Engineered VSVΔ51 expressing anti-PCSK9 single-chain variable fragments improves intra-tumor viral replication, sustains anti-tumor CD8<sup>+</sup> T cell memory, and enhances anti-PD-1 therapy efficacy. Our results identify the role of PCSK9 in the immunosuppressive feedback following viral infection and propose a strategy for engineered oncolytic virotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102724"},"PeriodicalIF":10.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589922","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}
{"title":"Out-of-frame CBX3::ALK fusion drives ALK activation and therapy response.","authors":"Jen-Fan Hang, Han-Ying Cheng, Yu-Shuen Tsai, Sin-Ying Lin, Jie-Hong Song, Chih-Hung Chung, Muh-Hwa Yang","doi":"10.1016/j.xcrm.2026.102697","DOIUrl":"10.1016/j.xcrm.2026.102697","url":null,"abstract":"<p><p>Kinase gene fusions are critical oncogenic drivers and key targets in precision oncology. Here, we report a CBX3::ALK out-of-frame fusion identified in a case of metastatic melanoma, which produces functional ALK isoforms via alternative translation start sites. The patient demonstrates a remarkable clinical response to the ALK inhibitor alectinib. Functional studies confirm that the CBX3::ALK-derived isoforms retain oncogenic signaling and tumorigenic potential. Our findings reveal limitations in current tertiary analysis strategies for functional gene fusion detection that may overlook clinically relevant out-of-frame fusions. Additional analysis of pan-cancer RNA sequencing data from 5,725 tumors and genomic datasets comprising 6,977 melanomas demonstrates that such events are rare but potentially significant. This study highlights the need to consider alternative translation mechanisms and incorporate additional analytic filters, such as 5'/3' expression imbalance, to better capture actionable out-of-frame fusion events in the era of precision oncology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102697"},"PeriodicalIF":10.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520157","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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