Cancer Science最新文献

{"title":"O-GlcNAcylation of KAT2A Enhances Bladder Cancer Proliferation by Inhibiting the KAT2A-TRIM22 Interaction","authors":"Wenjie Yang,&nbsp;Zhaoheng Jin,&nbsp;Ziyi Li,&nbsp;Weifeng Xu,&nbsp;Yingjie Li,&nbsp;Yueqiang Peng,&nbsp;Jie Dong,&nbsp;Lin Ma,&nbsp;Zhigang Ji","doi":"10.1111/cas.70416","DOIUrl":"10.1111/cas.70416","url":null,"abstract":"<p>Lysine acetyltransferase 2A (KAT2A) is a transcriptional coactivator and a member of the Histone Acetyltransferase (HAT) family. While altered KAT2A activity has been implicated in various cancers, its role in bladder cancer (BLCA) remains poorly understood. Post-translational modifications (PTMs), such as O-GlcNAcylation, play a critical role in cancer biology. In this study, we investigated the impact of O-GlcNAcylation on KAT2A stability and its oncogenic potential in BLCA. We analyzed 96 paired BLCA and normal tissue samples using quantitative real-time PCR (qPCR) and immunohistochemistry to assess KAT2A expression. Functional assays, including siRNA-mediated knockdown, co-immunoprecipitation (co-IP), ubiquitination, and chromatin immunoprecipitation (ChIP), were conducted in BLCA cell lines and xenograft models to understand KAT2A O-GlcNAcylation mechanisms. We found that KAT2A expression was significantly increased in BLCA tissues. O-GlcNAcylation at serine 583 (S583) stabilized KAT2A by inhibiting TRIM22-mediated ubiquitination. Hyper-O-GlcNAcylation increased H3K9 acetylation and upregulated oncogenes like TGFB1, E2F1, and GPX4, promoting cell proliferation and tumor growth. Mutation of S583 destabilized KAT2A, impaired H3K9 acetylation, and suppressed oncogene expression. Our results highlight the pivotal role of KAT2A in BLCA and demonstrate that O-GlcNAcylation at S583 is a crucial regulatory mechanism driving tumor progression. Targeting KAT2A O-GlcNAcylation may provide a promising therapeutic strategy for BLCA patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2166-2180"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876482","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":"Evolving Pathology of Anaplastic Thyroid Carcinoma: Integrating Morphology, Immunohistochemistry, and Molecular Insights","authors":"Toru Odate,&nbsp;Tetsuo Kondo","doi":"10.1111/cas.70427","DOIUrl":"10.1111/cas.70427","url":null,"abstract":"<p>Anaplastic thyroid carcinoma (ATC) is a rare malignancy characterized by an extremely aggressive clinical course, in contrast to the typically indolent behavior of most thyroid carcinomas. Recent advances in high-throughput sequencing technologies have markedly enhanced our understanding of the genetic alterations underlying ATC. These molecular insights have also influenced current clinical management and pathologic classification. In diagnostic pathology, squamous cell carcinoma arising in the thyroid is now recognized as a histologic variant of ATC. The <i>BRAF</i> p.V600E mutation, detected in approximately half of ATCs, represents a clinically significant genetic alteration, as targeted therapies directed against this mutation have been associated with improved clinical outcomes. In addition to advances in molecular pathology, progress has also been made in diagnostic pathology, including expanded recognition of the histologic spectrum of ATC and the development of novel immunohistochemical markers. In this review, we summarize recent advances in the diagnostic and molecular pathology of ATC, aiming to provide both fundamental and practical insights for clinical practice. In diagnostic pathology, ATC often presents significant challenges because of its marked histologic heterogeneity and a broad differential diagnosis. Accordingly, this review provides an overview of both classical knowledge and recent molecular findings related to ATC and integrates these insights to present an updated framework for differential diagnosis and diagnostic approach. In addition, we discuss recent advances in immunohistochemistry, including mutation-specific antibodies and novel diagnostic markers, and highlight their relevance in the context of contemporary diagnostic pathology and evolving therapeutic strategies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2029-2039"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044309","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":"Mutational Signature-Based Biomarker for Phase II Trial of Olaparib Maintenance in Advanced High-Grade Ovarian Cancer","authors":"Katsutoshi Oda,&nbsp;Daisuke Shintani,&nbsp;Akira Nishijima,&nbsp;Mayuyo Mori,&nbsp;Kazuyoshi Kato,&nbsp;Shoji Nagao,&nbsp;Noriomi Matsumura,&nbsp;Masahiro Kagabu,&nbsp;Masataka Takenaka,&nbsp;Kosuke Yoshihara,&nbsp;Yosuke Konno,&nbsp;Junzo Hamanishi,&nbsp;Sho Sato,&nbsp;Shiro Takamatsu,&nbsp;Keiko Ueda,&nbsp;Kosuke Kashiwabara,&nbsp;Takashi Aoki,&nbsp;Kunihiro Nishimura,&nbsp;Kenji Tatsuno,&nbsp;Hiroyuki Aburatani,&nbsp;Kosei Hasegawa","doi":"10.1111/cas.70421","DOIUrl":"10.1111/cas.70421","url":null,"abstract":"<p>We aimed to develop the mutational signature-based BioMarker (MSBM) to define homologous recombination deficiency (HRD) in newly diagnosed, advanced ovarian cancer and overcome limitations of genomic scar-based assays. We conducted a phase 2 trial (MSBM-OL) to evaluate the efficacy of olaparib maintenance monotherapy and to validate MSBM as a novel HRD biomarker. The MSBM was designed to integrate three whole-exome sequencing-derived features without using genomic scars: tumor-<i>BRCA</i> mutation status, Mutational Signature 3 similarity score &gt; 0.5, or score &gt; 0.25 without <i>CCNE1</i> amplification. Among 170 patients with stage IIIC/IV high-grade ovarian carcinoma, 58 HRD-positive patients responding to platinum-doublet chemotherapy (without bevacizumab) were enrolled. Thirty-two were randomized 2:1 to olaparib or placebo, and 26 enrolled after switching to a single-arm study. The primary endpoint was progression-free survival (PFS), evaluated against a predefined median of 9 months. Of 170 patients, 169 were evaluable for HRD (99.5%) and 123 (72.4%) were HRD-positive by MSBM, including 21.1% with tumor-<i>BRCA</i> mutations. The olaparib arm (<i>n</i> = 45) showed a median PFS of 22.3 months, significantly exceeding the 9-month threshold (<i>p</i> &lt; 0.001), meeting the primary endpoint. The placebo arm (<i>n</i> = 11) with a median PFS of 16.7 months was not powered for comparison. Grade ≥ 3 adverse events included anemia (25.5%) and neutropenia (12.8%). In a subset (<i>n</i> = 16), MSBM showed 81% concordance with myChoice CDx and correlated with genomic instability scores (<i>R</i> = 0.63). MSBM enables robust HRD evaluation from a whole-exome sequencing assay. Olaparib monotherapy demonstrated clinical benefit for first-line maintenance in HRD-positive ovarian cancer without bevacizumab.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2259-2273"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148018217","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":"First-In-Human Study: Dose Expansion of E7130 in Urothelial Carcinoma and Squamous Cell Carcinoma of the Head and Neck","authors":"Nobuaki Matsubara,&nbsp;Ken Saijo,&nbsp;Yasushi Shimizu,&nbsp;Susumu Okano,&nbsp;Kenji Nakano,&nbsp;Naoki Nishio,&nbsp;Tomoyuki Otsuka,&nbsp;Hirofumi Kuno,&nbsp;Takuma Miura,&nbsp;Tomoki Kubota,&nbsp;Hiroki Ikezawa,&nbsp;Yuko Umetsu,&nbsp;Ken Ito,&nbsp;Abraham Apfel,&nbsp;Yuanqing Ye,&nbsp;Yoshitaka Honma","doi":"10.1111/cas.70420","DOIUrl":"10.1111/cas.70420","url":null,"abstract":"<p>The dose escalation part of the first-in-human study of E7130 in patients with advanced solid tumors determined the Recommended Phase 2 Dose (RP2D) of E7130 (480 μg/m² Q3W). The dose expansion part (presented here) examined safety/preliminary efficacy in patients with squamous cell carcinoma of the head and neck (SCCHN) and urothelial carcinoma (UC). Patients ≥ 20 years of age with previously treated SCCHN/UC were treated at the RP2D. The primary objective was to characterize tolerability/safety. Secondary objectives included preliminary efficacy (including objective response rate [ORR], progression-free survival [PFS], and duration of response [DOR] by investigator per Response Evaluation Criteria In Solid Tumors version 1.1 [RECIST v1.1] and overall survival [OS]). Treatment-emergent adverse events (TEAEs) were recorded. In patients with SCCHN, tissue biomarker analyses were performed. Kaplan–Meier method was used to estimate PFS, DOR, and OS. The Greenwood formula and log–log transformation were used to estimate 95% CIs. Eight patients (SCCHN, <i>n</i> = 2; UC, <i>n</i> = 6) were treated with the RP2D; 10 additional patients (SCCHN, <i>n</i> = 7; UC, <i>n</i> = 3) were treated at a reduced dose (410 μg/m² Q3W). All patients had ≥ 1 TEAE; 66.7% had serious TEAEs. Patients with UC treated at the RP2D had an ORR of 66.7%; no other responses were observed. Median PFS/OS in patients with SCCHN treated at 480 μg/m² were 2.8/7.7 months and at 410 μg/m² were 3.5/5.0 months. Median PFS/OS in patients with UC treated at 480 μg/m² were 6.6/10.7 months and at 410 μg/m² were 2.6/11.9 months. Biomarker analyses indicated tumor microenvironment amelioration. Further evaluation is needed to optimize efficacy and safety of E7130 in patients with SCCHN and UC.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT03444701</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 8","pages":"2247-2258"},"PeriodicalIF":4.9,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044237","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 Nationwide Central Diagnosis for Pediatric CNS Tumors in Japan: The JCCG Brain Tumor and Pathology Committees","authors":"Yoshiko Nakano,&nbsp;Junko Hirato,&nbsp;Takako Yoshioka,&nbsp;Tetsuya Takimoto,&nbsp;Sumihito Nobusawa,&nbsp;Kaishi Satomi,&nbsp;Ran Tomomasa,&nbsp;Seiji Yamada,&nbsp;Taku Homma,&nbsp;Shoh Sasaki,&nbsp;Ayako Yamazaki,&nbsp;Maki Sakaguchi,&nbsp;Yasuhide Takeuchi,&nbsp;Nei Fukazawa,&nbsp;Kai Yamasaki,&nbsp;Kohei Fukuoka,&nbsp;Yui Shinohara Kimura,&nbsp;Yuki Nagayama,&nbsp;Yohei Inoue,&nbsp;Akira Miyahira,&nbsp;Ema Yoshioka,&nbsp;Asako Katsuma,&nbsp;Hayato Fukusumi,&nbsp;Tomoko Shofuda,&nbsp;Yuko Hibiya,&nbsp;Yuko Matsushita,&nbsp;Mai Honda Kitahara,&nbsp;Yuki Yomoda,&nbsp;Miho Kato,&nbsp;Michael D. Taylor,&nbsp;Yasuhito Arai,&nbsp;Tatsuhiro Shibata,&nbsp;Hiroaki Sakamoto,&nbsp;Keita Terashima,&nbsp;Yoshiki Arakawa,&nbsp;Toshihiro Kumabe,&nbsp;Ryo Nishikawa,&nbsp;Junichi Hara,&nbsp;Yonehiro Kanemura,&nbsp;Koichi Ichimura","doi":"10.1111/cas.70392","DOIUrl":"10.1111/cas.70392","url":null,"abstract":"<p>In 2016, the Japan Children's Cancer Group launched a nationwide research initiative to provide central diagnosis incorporating pathology review and molecular profiling for pediatric central nervous system (CNS) tumors. Over the first eight years, 2224 cases were registered. Non–next-generation sequencing analyzes, such as pyrosequencing and NanoString, were routinely performed, mainly for glioma, medulloblastoma, and ependymoma. Additional analyzes, including methylation profiling and RNA sequencing, were conducted for selected diagnostically challenging cases. The most common diagnoses were low-grade glioma (26%), medulloblastoma (18%), germ cell tumor (16%), high-grade glioma (12%), and ependymoma (11%). Diagnostic or targetable alterations were detected in nearly half of the glioma samples. Among medulloblastomas, Group 4 was the most prevalent subgroup (48%), followed by SHH-activated (28%), Group 3 (14%), and WNT-activated (11%). Among ependymomas, 95% of posterior fossa ependymomas were classified as PFA, and 72% of supratentorial ependymomas were positive for <i>ZFTA</i> fusion. Methylation-based classification enabled diagnostic refinement and identification of recently recognized novel subtypes. The integration of histopathological review by central pathologists and detailed molecular analyzes facilitated the recognition of rare tumors not yet defined in the World Health Organization classification. Our experience underscores the value of integrated diagnosis, which is now regarded as standard practice for pediatric CNS tumors, and highlights the urgent need for a sustainable clinical framework that incorporates molecular testing. This report represents the first comprehensive overview of the pediatric CNS tumor landscape in Japan in the molecular era.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1975-1984"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70392","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786310","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":"AKR1C3 Binds β-Trcp to Promote the Degradation of TFRC to Protect Hepatocellular Carcinoma From Ferroptosis","authors":"Lei Qi,&nbsp;Jingyi Hua,&nbsp;Di Pan,&nbsp;Wanwan Yang,&nbsp;Geng Tian,&nbsp;Fangyu Ye,&nbsp;Lingxiang Liu,&nbsp;Yuhan Mao,&nbsp;Qinglong Guo,&nbsp;Haopeng Sun,&nbsp;Li Zhao","doi":"10.1111/cas.70403","DOIUrl":"10.1111/cas.70403","url":null,"abstract":"<p>Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, represents a new potential therapeutic target in cancer. However, emerging evidence indicates that hepatocellular carcinoma (HCC) frequently exhibits resistance to ferroptosis induction, while the underlying molecular mechanism is poorly understood. Here, we found that aldo-keto reductase family 1 member C3 (AKR1C3), a protein highly expressed in ferroptosis-resistant HCC cells, negatively regulates ferroptosis in an enzyme-independent manner. Mechanistically, AKR1C3 promotes ubiquitin-proteasomal degradation of the transferrin receptor (TFRC), which is indispensable for cellular iron uptake. AKR1C3 knockdown restores TFRC expression, increases the level of labile iron pool, and sensitizes HCC cells to ferroptosis. Furthermore, AKR1C3 acts as a scaffolding protein to promote the degradation of TFRC and reduce iron uptake by promoting nuclear export of Beta-transducin repeats-containing proteins (β-TrCP) and its binding to TFRC. Notably, AKR1C3 is upregulated in NRF2-driven sorafenib-resistant HCC, and its inhibition reversed ferroptosis and sorafenib resistance. Our work uncovers AKR1C3 suppresses ferroptosis in HCC by promoting β-TrCP-mediated TFRC degradation, positioning AKR1C3 as a promising therapeutic target to enhance ferroptosis-based anticancer strategies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1867-1882"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822509","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":"Triple-Mutated HSV-1 Expressing Soluble B7-1 Plus CTLA-4 Blockade Suppresses Lymph Node Metastasis in Tongue Cancer","authors":"Akinari Sugauchi,&nbsp;Toshihiro Uchihashi,&nbsp;Hirotaka Ito,&nbsp;Miwako Iwai,&nbsp;Yuzuri Tsurumaki Sato,&nbsp;Kyoko Kurioka,&nbsp;Sena Zeynep Usta,&nbsp;Minoru Tanaka,&nbsp;Mikihiko Kogo,&nbsp;Susumu Tanaka,&nbsp;Hiroshi Fukuhara,&nbsp;Tomoki Todo","doi":"10.1111/cas.70410","DOIUrl":"10.1111/cas.70410","url":null,"abstract":"<p>Cervical lymph node metastasis is a major predictor of poor prognosis in patients with oral squamous cell carcinoma (OSCC), underscoring the need for therapies that effectively target metastatic spread. We previously reported that G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), rapidly traffics from tongue tumors to cervical lymph nodes and suppresses metastasis in murine models. Based on this lymphotropic property and the immunological significance of CD28–B7-1 interactions for T-cell activation, we pursue the potential of T-mB7-1, a new G47Δ-derived oncolytic HSV-1 expressing soluble murine B7-1. T-mB7-1 secreted soluble B7-1 in vitro without compromising cytopathic activity. In vivo, intratumoral T-mB7-1 suppressed tumor growth in the resistant KLN205-MUC1 subcutaneous model and prolonged survival in SCCVII orthotopic tongue tumors. In the KLN205-MUC1 orthotopic tongue cancer that exhibits rapid lymphatic metastasis, a single dose of T-mB7-1, but not the control virus T-01, significantly reduced cervical lymph node metastasis and improved survival. Repeated low-dose T-mB7-1 further caused near-complete suppression of lymph node metastasis and markedly extended survival. Flow cytometry showed both T-01 and T-mB7-1 induced CD69⁺ T-cell activation in cervical lymph nodes at 18 h, which was reduced with T-mB7-1 at 24 h. Importantly, combining T-mB7-1 with systemic CTLA-4 blockade markedly prolonged survival of mice harboring orthotopic KLN205-MUC1 tumors, with all treated mice surviving beyond 80 days in the otherwise fatal model. These findings demonstrate that soluble B7-1-expressing oncolytic HSV-1 combined with CTLA-4 blockade durably suppresses lymph node metastasis, providing a promising and minimally invasive strategy for regionally metastatic OSCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1961-1974"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845010","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":"TONSL Promotes Hepatocellular Carcinoma Progression by Inhibiting Apoptosis Through Homologous Recombination Repair","authors":"Akinori Tsujimoto,&nbsp;Hajime Otsu,&nbsp;Takashi Ofuchi,&nbsp;Tomohiko Ikehara,&nbsp;Kosuke Hirose,&nbsp;Shohei Shibuta,&nbsp;Kazuki Omachi,&nbsp;Yu Takahashi,&nbsp;Yuya Ono,&nbsp;Satoshi Higuchi,&nbsp;Takanari Tatsumi,&nbsp;Kiyotaka Hosoda,&nbsp;Qingjiang Hu,&nbsp;Yusuke Yonemura,&nbsp;Takaaki Masuda,&nbsp;Masayuki Sho,&nbsp;Koshi Mimori","doi":"10.1111/cas.70386","DOIUrl":"10.1111/cas.70386","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is an extremely aggressive type of cancer with a poor prognosis and is often associated with amplification of chromosome 8q. Tonsoku-like DNA repair protein (TONSL) gene, located on 8q, plays a role in repairing DNA double-strand breaks. However, its functional relevance in HCC is not yet fully understood. In this study, we investigated the biological significance of TONSL in HCC progression. Analyses of public datasets and clinical specimens revealed that TONSL expression was markedly elevated in tumor tissues. TONSL levels showed a positive correlation with copy number variation and high levels were significantly associated with unfavorable patient outcomes. Functional assays demonstrated that TONSL knockout substantially reduced cell growth and increased apoptosis. Mechanistically, loss of TONSL impaired the recruitment of RAD51 to DNA damage sites, resulting in defective homologous recombination repair and enhanced apoptotic activity. Furthermore, TONSL-knockout HCC cells showed increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitor. In a xenograft model, tumors generated from TONSL-knockout cells exhibited significantly reduced growth, underscoring the importance of TONSL in promoting HCC progression. Collectively, these findings indicate that TONSL facilitates HCC development by supporting RAD51-mediated DNA repair and suppressing apoptosis, and its elevated expression serves as a marker of poor prognosis. Thus, TONSL represents a promising biomarker of tumor aggressiveness and a potential therapeutic target in HCC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1852-1866"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70386","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786535","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":"Oncolytic Vaccinia Virus-HSP70-shRNA Amplifies Viral Replication, ROS/Autophagy, and Immunity to Fight Colorectal Cancer","authors":"Rentao Yuan,&nbsp;Ruikang Liu,&nbsp;Fangying Shao,&nbsp;Zheqi Cai,&nbsp;Yingfei Fang,&nbsp;Kan Chen,&nbsp;Yanrong Zhou,&nbsp;Ting Ye,&nbsp;Gongchu Li","doi":"10.1111/cas.70389","DOIUrl":"10.1111/cas.70389","url":null,"abstract":"<p>Colorectal cancer persists as a major contributor to cancer mortality, with immunotherapy offering limited efficacy in immunologically “cold” tumors. To address this issue, we engineered an oncolytic vaccinia virus to express HSP70 shRNA within its TK gene locus (oncoVV-shHSP70). In vitro, oncoVV-shHSP70 significantly suppressed HSP70 expression, enhanced viral replication, and induced apoptosis in CRC cells via Caspase-7/9 activation and Bcl-2 downregulation. OncoVV-shHSP70 also triggered reactive oxygen species (ROS) accumulation by suppressing the antioxidant regulator Nrf2 and stimulated autophagy via the Beclin-1/Vps34 pathway. Notably, a mutually reinforcing cycle between ROS overproduction and autophagy amplified the oncolytic effects of oncoVV-shHSP70, enhancing viral production, promoting apoptosis, and increasing cytokine release. Specifically, oncoVV-shHSP70 boosted cytokine production (TNF-α, IFN-α/β) through ROS/autophagy-dependent activation of AP-1 and IRF-3/7 pathways. In xenograft mouse models, oncoVV-shHSP70 induced cellular necrosis and significantly inhibited tumor growth. These findings demonstrate that oncoVV-shHSP70 enhances antitumor immunity in both syngeneic and humanized mouse models by promoting T-cell and dendritic-cell infiltration and inducing immunogenic cell death. In summary, oncoVV-shHSP70 emerges as a promising multimodal therapy for CRC, leveraging viral oncolysis, apoptosis induction, and immunomodulation to overcome therapeutic resistance.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"2007-2020"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70389","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786452","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":"Population-Based Identification of Clonal Hematopoiesis Using Peripheral Blood Whole-Genome Sequencing in Japan","authors":"SungGi Chi,&nbsp;Ikuko N. Motoike,&nbsp;Takao Fujisawa,&nbsp;Yumi Yamaguchi-Kabata,&nbsp;Takahiro Nobukuni,&nbsp;Kengo Kinoshita,&nbsp;Yoshiaki Nakamura,&nbsp;Hideaki Bando,&nbsp;Takayuki Yoshino,&nbsp;Kinuko Ohneda,&nbsp;Katsuya Tsuchihara,&nbsp;Yosuke Minami,&nbsp;Riu Yamashita","doi":"10.1111/cas.70406","DOIUrl":"10.1111/cas.70406","url":null,"abstract":"<p>Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition whose population-level characteristics and clinical concordance in Japan remain incompletely defined. We analyzed whole-genome sequencing data from 49,982 participants in the Tohoku Medical Megabank (TMM) cohort to characterize the prevalence, mutational spectrum, age dependency, and clinical relevance of CHIP. CHIP mutations were detected in 1234 individuals (2.5%), comprising 1413 variants across 1015 loci. <i>DNMT3A</i> and <i>TET2</i> were the most frequently mutated genes, whereas <i>ASXL1</i> and <i>PPM1D</i> mutations were less prevalent than reported in Western cohorts. Four recurrent CHIP candidate loci (<i>ZNF318</i>, <i>SMC3</i>, <i>CBL</i>, and <i>GNAS</i>) were identified, most of which were predicted to be oncogenic. Comparison with TOPMed and UK Biobank datasets demonstrated overall concordance in variant prevalence, with differences observed for selected driver mutations. dN/dS analysis indicated positive selection in the majority of CHIP-associated genes. Concordance with clonal hematopoiesis (CH) mutations detected in cancer patients was evaluated using data from the MONSTAR-SCREEN-2 study with paired leukocyte sequencing. When focusing on genes in which CHIP mutations have been reported, 66% were confirmed as CH, yielding a positive predictive value of 66% and a negative predictive value of 76%. CHIP prevalence increased significantly with age, exceeding 5% in individuals aged ≥ 70 years, with an estimated 3.4% increase per additional year of age. Higher variant allele frequency mutations showed a slightly stronger age association. These findings define the landscape of CHIP in the Japanese population and clarify its relationship to CH detected by cancer-focused liquid biopsy assays.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1996-2006"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70406","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786541","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}