Cancer letters最新文献

{"title":"Drug-tolerant persisting polyploid giant cancer cells mediate resistance to HER2-targeting antibody-drug conjugates.","authors":"Narjes Yazdi, Negar Pourjamal, Riku Katainen, Juho Väänänen, Jun Dai, Anna Vähärautio, Jorma Isola, Minna Kempas, Vadim Le Joncour, Pirjo Laakkonen, Heikki Joensuu, Mark Barok","doi":"10.1016/j.canlet.2025.217900","DOIUrl":"10.1016/j.canlet.2025.217900","url":null,"abstract":"<p><p>Polyploid giant cancer cells (PGCCs) contribute to resistance against various cancer therapies. This study investigates whether HER2-directed antibody-drug conjugates (ADC) induce PGCCs and their role in drug resistance. HER2-positive breast cancer (JIMT-1) and gastric cancer (MKN7, SNU-216) cells were treated with HER2-directed ADCs, trastuzumab emtansine, trastuzumab deruxtecan, XMT-1522, and disitamab vedotin (DV). The induced persister cells were characterized using live cell imaging, confocal microscopy, immunohistochemistry, flow cytometry, gene expression analysis, SNP genotyping, and next-generation sequencing. Drug sensitivity was assessed using the AlamarBlue assay and SCID mouse xenografts. All 4 ADCs induced PGCCs, with XMT-1522 and DV being the most effective. The induced giant cells were drug-resistant and exhibited drug-tolerant persister cell characteristics. HER2 protein levels were downregulated in persisting drug-tolerant PGCCs and their daughter cells. JIMT-1 cells lost HER2 amplification following XMT-1522 treatment, along with the loss of extrachromosomal DNA containing HER2. However, XMT-1522-treated MKN7 and SNU-216 cells, and DV-treated JIMT-1 cells, retained the amplicon. Drug-tolerant PGCCs upregulated nectin-4, and treatment with enfortumab vedotin, a nectin-4-targeted ADC, inhibited the regrowth of JIMT-1 xenografts. ADC treatment induces PGCCs that contribute to drug resistance. ADC-induced drug-tolerant PGCCs express nectin-4, which may serve as a potential therapeutic target.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217900"},"PeriodicalIF":9.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564618","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":"The pro-apoptotic peptide PEP-010 triggers apoptosis in pancreatic tumor models in monotherapy and in combination with gemcitabine independently of the KRAS status","authors":"Aline Lacroix ,&nbsp;Léa Swales ,&nbsp;Rayan Farhat ,&nbsp;Laura Dadon ,&nbsp;Gyunel Rashidova ,&nbsp;Laurane Lhoste ,&nbsp;Jérôme Cartry ,&nbsp;Jacques R.R. Mathieu ,&nbsp;Alice Boileve ,&nbsp;Fanny Jaulin ,&nbsp;Joëlle Wiels ,&nbsp;Catherine Brenner ,&nbsp;Diego Germini","doi":"10.1016/j.canlet.2025.217896","DOIUrl":"10.1016/j.canlet.2025.217896","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217896"},"PeriodicalIF":9.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144557589","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":"Strategic radiotherapy: a new proof of concept.","authors":"Francesca De Felice, Giuseppe Minniti","doi":"10.1016/j.canlet.2025.217897","DOIUrl":"10.1016/j.canlet.2025.217897","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217897"},"PeriodicalIF":9.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552396","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":"Corrigendum to \"Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer\" [Cancer Lett 609 (2025) 217352].","authors":"Loïc Steiner, Maria Eldh, Annemarijn Offens, Rosanne E Veerman, Markus Johansson, Tammer Hemdan, Hans Netterling, Ylva Huge, Abdul-Sattar Aljabery Firas, Farhood Alamdari, Oskar Lidén, Amir Sherif, Susanne Gabrielsson","doi":"10.1016/j.canlet.2025.217876","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217876","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217876"},"PeriodicalIF":9.1,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526456","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":"Unraveling the dual nature of FLASH radiotherapy: From normal tissue sparing to tumor control","authors":"Yulu Guo ,&nbsp;Sijia Hao ,&nbsp;Qiaozhen Huang ,&nbsp;Cuixia Di ,&nbsp;Lu Gan ,&nbsp;Yi Xie ,&nbsp;Qiang Li ,&nbsp;Jing Si","doi":"10.1016/j.canlet.2025.217895","DOIUrl":"10.1016/j.canlet.2025.217895","url":null,"abstract":"<div><div>FLASH radiotherapy (FLASH-RT), characterized by the delivery of ultra-high dose rate irradiation within microseconds to milliseconds, has rapidly emerged as a paradigm-shifting approach in radiation oncology. Preclinical studies have consistently demonstrated its remarkable ability to spare normal tissues while maintaining effective tumor control, challenging long-standing paradigms of radiobiology. This review comprehensively synthesizes current experimental findings from diverse in vitro and in vivo models, including zebrafish embryos, mice, <em>Drosophila melanogaster</em>, and <em>Caenorhabditis elegans</em>, emphasizing the distinct protective effects of FLASH-RT across various tissue types. Potential mechanistic hypotheses—such as radiolytic oxygen depletion, radical recombination, immune modulation, mitochondrial dynamics, and preservation of DNA integrity—are critically evaluated to illuminate the biological foundations of the FLASH effect. Furthermore, the influence of key technical parameters, including radiation modality, total dose, dose rate, and fractionation schemes, alongside biological determinants such as tissue radiosensitivity and tumor heterogeneity, is systematically analyzed. Despite the promising preclinical evidence, major challenges persist in optimizing radiation delivery protocols, unraveling the precise biological mechanisms, and translating these findings into clinical practice. As a highly anticipated and transformative therapeutic innovation, FLASH-RT holds tremendous potential to redefine the future of cancer treatment; however, its underlying mechanisms remain elusive and continue to be a focal point of intensive multidisciplinary research.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217895"},"PeriodicalIF":9.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523262","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":"Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer","authors":"Enkui Zhang ,&nbsp;Xinjia Ding ,&nbsp;Jixin Zhang ,&nbsp;Weikang Liu ,&nbsp;Guangnian Liu ,&nbsp;Mingzhe Li ,&nbsp;Xinxin Liu ,&nbsp;Yingjin Wang ,&nbsp;Fusheng Zhang ,&nbsp;Baoyi Li ,&nbsp;Yu Zhu ,&nbsp;Yupeng Yan ,&nbsp;Jiayu Liu ,&nbsp;Yuxin Wang ,&nbsp;Xiaodong Tian ,&nbsp;Yongsu Ma ,&nbsp;Yinmo Yang","doi":"10.1016/j.canlet.2025.217887","DOIUrl":"10.1016/j.canlet.2025.217887","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic reprogramming, with polyamine metabolism emerging as a key driver of tumor progression and immune evasion. However, its comprehensive role and clinical significance in PDAC remain largely unexplored. We performed an integrative analysis using bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and functional assays to systematically characterize polyamine metabolism in PDAC. A polyamine metabolism-based prognostic model (PMscore) was developed via principal component analysis, and key regulatory genes were identified using a random forest algorithm. Functional studies in vitro and in vivo assessed the role of NT5E (CD73), a core gene involved in polyamine metabolism, in tumor biology and the tumor microenvironment (TME). Polyamine metabolism was markedly upregulated in PDAC and associated with poor prognosis. The PMscore effectively stratified patients into three prognostic subgroups and was predictive of metabolic and immune features. NT5E was identified as a critical regulator, highly expressed in epithelial and mesenchymal cells. Its knockdown impaired polyamine metabolism, reduced tumor cell proliferation and migration, and altered TME composition. Notably, CD73⁺ cancer-associated fibroblasts (CAFs) were enriched near tumor cells, suggesting their involvement in metabolic crosstalk and immunosuppression. Our study provides a comprehensive multi-omics characterization of polyamine metabolism in PDAC. NT5E serves as a key metabolic and immunoregulatory gene, representing a promising biomarker and therapeutic target. Combined inhibition of NT5E and polyamine metabolism may offer a novel strategy to suppress tumor progression and modulate the immunosuppressive TME in PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217887"},"PeriodicalIF":9.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518420","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":"Pancreatic cancer cells survive in the neural niche during neoadjuvant therapy","authors":"Kaan Çifcibaşı ,&nbsp;Ruediger Goess ,&nbsp;Enkhtsetseg Munkhbaatar ,&nbsp;Ilaria Pergolini ,&nbsp;Carsten Jäger ,&nbsp;Alexander Muckenhuber ,&nbsp;Helmut Friess ,&nbsp;Güralp Onur Ceyhan ,&nbsp;Rouzanna Istvanffy ,&nbsp;Ihsan Ekin Demir ,&nbsp;Carmen Mota Reyes","doi":"10.1016/j.canlet.2025.217894","DOIUrl":"10.1016/j.canlet.2025.217894","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217894"},"PeriodicalIF":9.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518421","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":"Innate lymphoid cells in pancreatic ductal adenocarcinoma: Immune regulation and therapeutic implications","authors":"Tinghui Mao ,&nbsp;Wenjiao Teng ,&nbsp;Li Lin ,&nbsp;Wei Zhou","doi":"10.1016/j.canlet.2025.217890","DOIUrl":"10.1016/j.canlet.2025.217890","url":null,"abstract":"<div><div>Over the past two decades, immunotherapy has revolutionized cancer treatment by shifting our strategies to harness the body's own immune system, with the promise of inhibiting or even eliminating tumors through methods that control and enhance immune responses. Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, features an immunosuppressive tumor immune microenvironment (TIME) that serves as the core factor contributing to poor prognosis of patients. Emerging research has unveiled the dual role of innate lymphoid cells (ILCs), acting as tissue-resident innate immune hubs, in PDAC immune regulation through their dynamic plasticity, heterogeneity, and interactions with various adaptive immune cells. This review systematically summarizes the latest research advancements in the developmental plasticity of ILC subsets and their bidirectional regulatory network in PDAC, highlighting the potential value of targeting ILCs to reshape the PDAC TIME. Future research should integrate single-cell multi-omics technologies to dissect the spatiotemporal heterogeneity of ILCs, develop strategies to activate their anti-tumor activity, and explore synergistic approaches combining chimeric antigen receptor (CAR)-NK cell therapy with existing immunotherapies, providing new paradigms for transforming PDAC from an immunologically \"cold\" tumor to an immune-sensitive one.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217890"},"PeriodicalIF":9.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502789","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":"The significance of protein N-glycosylation in the pathogenesis of lung cancer and its clinical implications","authors":"Yibo Huang ,&nbsp;Jin Song ,&nbsp;Jinfeng Chen ,&nbsp;Feng Li ,&nbsp;Yi Zhang ,&nbsp;Jing-Hua Yang","doi":"10.1016/j.canlet.2025.217849","DOIUrl":"10.1016/j.canlet.2025.217849","url":null,"abstract":"<div><div>This comprehensive review systematically elucidates the multifaceted roles of protein N-glycosylation in lung cancer pathogenesis, including its contributions to accelerated cell proliferation, enhanced metastatic potential, promotion of epithelial‒mesenchymal transition (EMT), maintenance of stem cell characteristics, facilitation of immune evasion, preservation of angiogenesis, and diminished drug sensitivity. Additionally, the potential clinical utility of aberrant N-glycosylation is examined as a novel biomarker for early diagnosis, prognostic evaluation, and treatment monitoring in lung cancer. The analysis highlights the critical involvement of N-glycosylation in chemotherapy resistance, targeted therapy, and immunotherapy, offering new perspectives for the development of innovative therapeutic strategies. Furthermore, this review highlights promising applications of antibody-enzyme engineering technology in achieving more precise lung cancer treatments, introducing new opportunities for the field. These findings provide a significant theoretical basis and experimental evidence to support progress in lung cancer research and treatment advancements.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217849"},"PeriodicalIF":9.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511601","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":"CD51 promotes gastric cancer stemness via blocking Numb-mediated Notch1 degradation","authors":"Juzheng Peng ,&nbsp;Yuehan Yin ,&nbsp;Xuan Liu ,&nbsp;Cuncan Deng ,&nbsp;Peizhu Wang ,&nbsp;Xiaojie Hu ,&nbsp;Jiefu Chen ,&nbsp;Sicheng Peng ,&nbsp;Kuan Li ,&nbsp;Li Zhong ,&nbsp;Zhijun Zhou ,&nbsp;Yulong He ,&nbsp;Jiancheng Wang","doi":"10.1016/j.canlet.2025.217886","DOIUrl":"10.1016/j.canlet.2025.217886","url":null,"abstract":"<div><div>Gastric cancer (GC) remains a lethal malignancy with poor prognosis largely due to cancer stem cell (CSC)-driven metastasis, recurrence, and chemoresistance. This study identifies CD51 (integrin αv) as a pivotal regulator of GC stemness and malignant progression. Bioinformatics analysis of TCGA data revealed significant CD51 upregulation in GC tissues, correlating with advanced tumor stage and poor survival. Functional assays demonstrated that CD51 enhances CSC properties, including tumorsphere formation, migration, invasion, and oxaliplatin resistance. Mechanistically, CD51 interacts with Numb, a negative regulator of Notch signaling, to divert Notch1 receptor trafficking from lysosomal degradation to plasma membrane recycling, thereby amplifying Notch pathway activation. Single-cell RNA sequencing and clinical validations confirmed CD51's superior correlation with stemness scores compared to canonical CSC markers. Pharmacological inhibition of CD51 using cilengitide suppressed CSC phenotypes in vitro and inhibited tumor growth in patient-derived organoids and xenograft models. These findings establish CD51 as a novel CSC biomarker and therapeutic target, offering a strategy to disrupt Notch-dependent stemness and chemoresistance in GC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217886"},"PeriodicalIF":9.1,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483247","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}