Cancer Science最新文献

{"title":"Utility of Urinary Extracellular Vesicles for Colorectal Cancer: Comparison of DNA Quality and MRD Detection.","authors":"Shintaro Kanaka, Takeshi Yamada, Fumi Asai, Yuta Shimizu, Kay Uehara, Akihisa Matsuda, Seiichi Shinji, Yasuyuki Yokoyama, Goro Takahashi, Takuma Iwai, Kohki Takeda, Sho Kuriyama, Toshimitsu Miyasaka, Koki Hayashi, Hiroshi Yoshida","doi":"10.1111/cas.70368","DOIUrl":"https://doi.org/10.1111/cas.70368","url":null,"abstract":"<p><p>This study evaluated the feasibility of urinary extracellular vesicles (EVs) as a liquid biopsy source for colorectal cancer (CRC) using two predefined cohorts: 97 patients for analytical validation and 63 patients for postoperative survival analysis. We compared urinary EVs, urinary cell-free tumor DNA (ctDNA), plasma EVs, and plasma ctDNA across multiple molecular dimensions, and assessed the utility of urinary EV-DNA for minimal residual disease (MRD) detection. Urinary EVs exhibited larger particle size (median 175.6 nm) and markedly higher purity, demonstrated by a substantially broader proteomic profile (4674 vs. 476 proteins) and significantly higher expression of EV-specific markers (CD63, CD81, CD9). DNA extracted from urinary EVs showed the highest concentration and best preservation of nucleic acid integrity, with the greatest Long/Short fragment ratio, outperforming all plasma-derived samples. Mutation detection sensitivity was comparable across sample types but was highest in plasma ctDNA (39.2%) and urinary EV-DNA (34.0%), exceeding urinary ctDNA (21.6%). In the survival cohort, MRD positivity-defined as detectable RAS/BRAF mutations in urinary EV-DNA 1 month after curative surgery-was strongly associated with inferior outcomes (HR for recurrence 5.25, 95% CI 1.74-15.80), and overall survival was significantly worse in MRD-positive patients. These findings indicate that urinary EVs provide highly pure vesicles with superior DNA quality, making them a robust and completely non-invasive source for molecular profiling. Urinary EV-DNA-based MRD assessment shows significant prognostic value and may serve as a practical tool for postoperative monitoring and risk stratification in colorectal cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOD2-Superoxide Metabolic Axis Regulates Mitophagy and Modulates TKIs Sensitivity in Head and Neck Squamous Cell Carcinoma.","authors":"Wan-Hang Zhou, Shuo-Jin Huang, An-Xun Wang","doi":"10.1111/cas.70374","DOIUrl":"https://doi.org/10.1111/cas.70374","url":null,"abstract":"<p><p>Superoxide dismutase 2 (SOD2) has been implicated in head and neck squamous cell carcinoma (HNSCC), yet its mechanistic contribution in regulating tumor responses to tyrosine kinase inhibitors (TKIs) remains unclear. Here, we investigated whether SOD2 shapes TKI sensitivity in HNSCC through a mitochondrial superoxide-mitophagy axis. Bioinformatic analyses revealed that elevated SOD2 expression was negatively correlated with mitophagy signatures in HNSCC. Functional experiments showed that SOD2 silencing led to mitochondrial superoxide accumulation, impaired mitochondrial function, and significant mitophagy activation in HNSCC cells. Pharmacological modulation further supported a superoxide-dependent mechanism, as Mito-TEMPO suppressed mitochondrial superoxide and mitophagy induction, whereas rotenone enhanced mitochondrial superoxide and mitophagy activity. Importantly, SOD2 knockdown increased apoptotic susceptibility and sensitized HNSCC cells to TKI treatment, which was partially reversed by superoxide scavenging but reinforced by superoxide elevation. Consistently, SOD2 knockout xenograft models exhibited enhanced antitumor responsiveness to TKIs in vivo. Collectively, these findings identified SOD2 as a key regulator of mitochondrial redox homeostasis and mitophagy, thereby modulating therapeutic sensitivity in HNSCC, and suggest that targeting the SOD2-superoxide metabolic axis may represent a promising strategy to improve TKIs efficacy in HNSCC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147582007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EMB-01, a Tetravalent Bispecific Antibody, Inducing Co-Degradation of EGFR and c-Met for Enhanced Anti-Tumor Efficacy.","authors":"Jing Gao, Xi Jiao, Fang Ren, Xuan Wu, Jingyun Tan, Yuezong Bai, Yan Dai, Lixia Shen, Chengbin Wu, Lin Shen","doi":"10.1111/cas.70280","DOIUrl":"10.1111/cas.70280","url":null,"abstract":"<p><p>The bispecific antibody EMB-01 (bafisontamab), constructed using EpimAb's proprietary FIT-Ig platform, is designed to simultaneously target epidermal growth factor receptor (EGFR) and receptor tyrosine kinase Met (c-Met). Here, we characterize EMB-01's binding properties, mechanisms of action, and anti-tumor efficacy using in vitro cell line models and in vivo models (patient-derived xenografts, PDXs). EMB-01 exhibits high-affinity binding to EGFR and c-Met, induces co-degradation of both receptors, enhances endocytosis, and elicits strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effects. Mechanistically, EMB-01 effectively inhibits ligand-induced receptor phosphorylation, downstream AKT activation, and IL-8 secretion. Furthermore, EMB-01 demonstrates potent anti-tumor activity across multiple tumor models, outperforming existing EGFR-targeted therapies and other bispecific antibodies, while maintaining favorable pharmacokinetics with good tolerability in cynomolgus monkeys. These findings support the clinical development of EMB-01 as a promising therapeutic for EGFR/c-Met-driven cancers.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"807-817"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-Phenotype Correlations of Li-Fraumeni Syndrome in Japan Children's Cancer Group LFS20 Study Cohort.","authors":"Fumito Yamazaki, Yoshiko Nakano, Masashi Sanada, Hiroki Kurahashi, Shunsuke Miyai, Arisa Ueki, Yuko Watanabe, Daisuke Hasegawa, Shuhei Karakawa, Toshifumi Ozaki, Akira Hirasawa, Akiko M Saito, Eisuke Inoue, Motohiro Kato, Hiroyoshi Hattori","doi":"10.1111/cas.70302","DOIUrl":"10.1111/cas.70302","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline pathogenic variants in the TP53 gene. With the increasing use of multi-gene panel testing, TP53 variants have been identified in individuals who do not meet established TP53 testing criteria, such as the Chompret criteria. The term \"attenuated LFS\" has been proposed for some of these cases, particularly those with adult-onset cancer. We analyzed participants of the Japanese nationwide prospective clinical trial of the cancer surveillance program (Japan Children's Cancer Group LFS-20), along with clinical information including their family histories, to better understand their genotypic and phenotypic characteristics. We identified 32 distinct TP53 variants from 41 families (45 participants), including four missense variants with conflicting classifications of pathogenicity in ClinVar. Among these families, 36 (88%) met the LFS criteria (hereafter referred to as \"LFS\" in contrast to attenuated LFS), while 5 (12%) were classified as attenuated LFS. Including 30 additional family members carrying the same variant, we analyzed 75 individuals with TP53 variants. Of these, 40 with LFS and 6 with attenuated LFS had cancer. Multiple primary cancers occurred in 22 individuals (21 LFS, 1 attenuated LFS). LFS-core tumors accounted for 66% (58/88) of cancers in the LFS group and 63% (5/8) in the attenuated LFS group; of note, all core tumors in the attenuated group were limited to breast cancer. Hotspot missense variants were detected in 11 of 36 LFS families and in none of 5 attenuated LFS families, and non-hotspot null variants were found in 14 and 1, respectively. Our study revealed genotype-phenotype correlations in several respects. UMIN-CTR: UMIN000045855.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"836-840"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Label Noise in Pathological Segmentation Is Overlooked, Leading to Potential Overestimation of Artificial Intelligence.","authors":"Kenji Harada, Yuichiro Nomura, Daisuke Komura, Shumpei Ishikawa, Shingo Sakashita","doi":"10.1111/cas.70288","DOIUrl":"10.1111/cas.70288","url":null,"abstract":"<p><p>Artificial intelligence (AI) has transformed medical imaging, notably in radiology and endoscopy. Semantic segmentation, a pixel-level technique crucial for delineating pathological features, has become pivotal in digital pathology. Pathology segmentation AI models are often trained using annotations generated by pathologists. Despite the meticulous care typically exercised, pathologist-generated annotations often contain label noise whose types and effects on model training remain underexplored. This study combined a survey of public datasets with the synthesis of artificial label noise to evaluate its effects on pathology segmentation models. Using publicly available datasets and a breast cancer semantic segmentation dataset, modules were developed to simulate four types of artificial label noise at varying intensity levels. These datasets were used to train deep learning models and their performance was evaluated. The results indicated that models were highly susceptible to overfitting label noise, particularly boundary-dependent noise, such as dilation and shrinkage. Discrepancies were identified between apparent performance scores obtained under real-world conditions and true performance scores derived using clean test data. This overestimation risk was most pronounced for datasets containing boundary-altering noise. Furthermore, random noise combinations further degraded generalization. This study underscores the critical importance of addressing label noise in pathology datasets. It is proposed that future efforts focus on developing standardized methods for quantifying and mitigating label noise, along with creating robust benchmarks using noise-inclusive datasets. Enhancing annotation quality and addressing label noise can improve the reliability and generalizability of AI in pathology, facilitating broader clinical adoption.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"852-863"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145821745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Transcriptomic Analysis of Cancer-Stromal Interactome in Lung Cancer Xenograft Models.","authors":"Yuriko Takayama-Isagawa, Daisuke Komura, Takayuki Isagawa, Yusuke Amano, Atsushi Kihara, Tamaki Miura, Taichiro Yoshimoto, Hiroyoshi Tsubochi, Kazutaka Fujita, Koichi Hagiwara, Makoto Maemondo, Tetsuo Ushiku, Shumpei Ishikawa, Noriyoshi Fukushima, Kentaro Inamura, Daisuke Matsubara, Toshiro Niki","doi":"10.1111/cas.70270","DOIUrl":"10.1111/cas.70270","url":null,"abstract":"<p><p>Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"841-851"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Programmed Death Ligand 1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cell Phenotypes in Hepatocellular Carcinoma Through the Serum and Glucocorticoid Kinase 2/β-Catenin Signaling Pathway\".","authors":"","doi":"10.1111/cas.70316","DOIUrl":"10.1111/cas.70316","url":null,"abstract":"","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"876-877"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Graph Neural Network-Based Multi-Scale Whole Slide Image Fusion for pT Staging of Muscle-Invasive Bladder Cancer.","authors":"Qian Li, Qing Feng Chen, Nan Qing Liao","doi":"10.1111/cas.70292","DOIUrl":"10.1111/cas.70292","url":null,"abstract":"<p><p>Accurate primary tumor (pT) staging in muscle-invasive bladder cancer (MIBC) is crucial for treatment and prognosis. Current methods require time-consuming, labor-intensive microscopic evaluation by pathologists, with inherent interobserver variability. There is a need for AI-driven automated diagnosis of whole-slide images (WSI) to improve diagnostic efficiency while maintaining accuracy in pT staging. We obtained 281 H&E-stained WSI samples from the TCGA dataset for developing and validating a graph neural network (GNN)-based diagnostic model, and 83 additional samples from a hospital for external validation. The GNN method integrated multi-scale WSI data, evaluated using areas under the curve (AUC), accuracy, sensitivity, and specificity. A multi-scale attention mechanism was added to enhance model interpretability by capturing pT staging infiltration patterns. Diagnostic results were compared with those of three pathologists of varying expertise. We developed the multi-scale WSI-integrated GNN model for histopathological staging (T2/T3/T4) of MIBC. The model demonstrated excellent performance on external validation, achieving an AUC of 0.911 and an accuracy of 0.905. Interpretability analysis revealed distinct infiltration patterns for each T-stage, while diagnostic comparisons against both ground truth and three independent pathologists showed strong agreement, with a Cohen's kappa coefficient exceeding 0.876. The model developed based on graph neural network methods can integrate multi-scale information from whole-slide tissue images, allowing it to capture key infiltration patterns for muscle-invasive bladder cancer pT staging. This enables precise pT staging and visualizes the multi-scale tumor infiltration regions through attention scores, with accuracy showing strong consistency with expert pathologists.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"864-875"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145821742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Senescence-Driven Heterogeneity in Early-Onset Colorectal Cancer for Prognostic and Therapeutic Stratification.","authors":"Du Cai, Mingru Mai, Rende Huang, Haoning Qi, Xingzhi Feng, Qianling Gao, Yinmeng Zhang, Chenghang Li, Xiaojian Wu, Yize Mao, Zihuan Yang, Feng Gao","doi":"10.1111/cas.70301","DOIUrl":"10.1111/cas.70301","url":null,"abstract":"<p><p>Early-onset colorectal cancer (EOCRC), diagnosed in patients under 50, is particularly aggressive, yet lacks targeted therapeutic strategies. This study aimed to explore the role of cellular senescence in driving EOCRC's malignancy and developed a senescence scoring system (EO-Senscore) to guide precision oncology. Through a multi-omics analysis of 2961 patients, we discovered that cellular senescence is more pronounced and varied in EOCRC and is not tied to chronological age. Two distinct senescence subtypes were identified: Cluster 1 (low-senescence tumors) showed prolonged survival, enhanced immunogenicity, and cell cycle activation, while Cluster 2 (high-senescence tumors) exhibited aggressive phenotypes and an immunosuppressive microenvironment. We further developed a machine learning model, the EO-Senscore, to quantify a tumor's senescence level. This score effectively stratified patients by prognosis and potential treatment response. Patients with a low EO-Senscore were predicted to respond well to immunotherapy and chemotherapy. In contrast, those with a high score had more invasive tumors but showed significant sensitivity to senolytic drugs (like ABT-263) in lab-based experiments. In conclusion, this research establishes cellular senescence as a crucial factor in EOCRC's aggressiveness. The EO-Senscore provides a practical, quantitative tool to guide clinical decisions, suggesting that patients could be directed toward immunotherapy or novel senolytic-based combination therapies for more personalized and effective cancer care.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"818-835"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145851261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}