Cancer Science最新文献

{"title":"Genomic Profiling of Pediatric Solid Tumors With a Dual DNA/RNA Panel: JCCG-TOP2 Study","authors":"Kayoko Tao,&nbsp;Takako Yoshioka,&nbsp;Miho Kato,&nbsp;Kazuyuki Komatsu,&nbsp;Shinichi Tsujimoto,&nbsp;Kenichi Sakamoto,&nbsp;Kazuki Tanimura,&nbsp;Minako Sugiyama,&nbsp;Masahiro Sekiguchi,&nbsp;Yoshiko Nakano,&nbsp;Yoshihiro Otani,&nbsp;Yasushi Yatabe,&nbsp;Akihiko Yoshida,&nbsp;Hajime Okita,&nbsp;Junko Hirato,&nbsp;Kenichi Kohashi,&nbsp;Yukichi Tanaka,&nbsp;Shinji Kohsaka,&nbsp;Takashi Kubo,&nbsp;Kuniko Sunami,&nbsp;Makoto Hirata,&nbsp;Shuichi Tsutsumi,&nbsp;Hiroyuki Aburatani,&nbsp;Katsuyoshi Koh,&nbsp;Masahiro Hirayama,&nbsp;Shuhei Karakawa,&nbsp;Yukayo Terashita,&nbsp;Hiroyuki Fujisaki,&nbsp;Takeshi Yagi,&nbsp;Akihiro Yoneda,&nbsp;Shinji Mochizuki,&nbsp;Hiroyuki Shichino,&nbsp;Tatsuya Suzuki,&nbsp;Tetsuya Takimoto,&nbsp;Koichi Ichimura,&nbsp;Chitose Ogawa,&nbsp;Kimikazu Matsumoto,&nbsp;Hitoshi Ichikawa,&nbsp;Motohiro Kato","doi":"10.1111/cas.70249","DOIUrl":"10.1111/cas.70249","url":null,"abstract":"<p>To develop an optimized genomic medicine platform for pediatric cancers, a nationwide cancer genome profiling project was conducted from January 2022 to February 2023 in collaboration with the Japan Children's Cancer Group. This prospective observational study analyzed matched blood and FFPE tumor samples from patients aged 0–29 years with solid tumors. Genomic analysis used the TOP2 hybrid capture–enrichment system, targeting 737 and 455 genes in the DNA and RNA panels, along with allele-specific genome copy number alterations. A total of 210 patients from 50 institutions were enrolled across Japan (median age, 8 years; range, 0–25). Of these, 154 (77%) were enrolled at diagnosis or during/after initial treatment and 56 (27%) at disease progression or relapse. The TOP2 findings had great benefits in clarifying the diagnosis of pediatric solid tumors. Among the 204 patients with genomic results, 147 (72%) had potentially actionable findings, including diagnostic, prognostic, and therapeutic findings in 111 (54%), 61 (30%), and 64 (31%), respectively. Oncogenic fusions were noted in 45 (23%) patients. A copy number alteration was identified in at least one genomic region in 170 (83%) patients. Two patients exhibited a high tumor mutation burden. Seventeen (8%) patients harbored a germline pathogenic/likely pathogenic variant in cancer-predisposing genes. This study highlighted the feasibility of implementing a nationwide precision medicine platform and the clinical utility of the TOP2 system for pediatric cancers. The results support the integration of genomic data into the standard clinical care of pediatric patients with cancer, both at diagnosis and at relapse.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"522-535"},"PeriodicalIF":4.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542824","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":"From Genomic and Epigenomic Maps to Medicines in Adult T-Cell Leukemia/Lymphoma","authors":"Kako Suzuki,&nbsp;Makoto Yamagishi","doi":"10.1111/cas.70245","DOIUrl":"10.1111/cas.70245","url":null,"abstract":"<p>Adult T-cell leukemia/lymphoma (ATL) is an aggressive and refractory hematologic malignancy that is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. ATL results from a combination of viral latency and the accumulation of abnormalities throughout the genome, epigenome, transcriptome, and signaling pathways. Despite numerous studies, the data have been largely fragmentary, and a comprehensive understanding of this disease remains unclear. Recent comprehensive analyses have contributed not only to the identification of fundamental molecular abnormalities in ATL, but also to the development of novel therapeutic strategies and prognostic models. In this review, an overview of the latest advances in the genomic, epigenomic, and transcriptomic alterations associated with ATL is provided, which highlights the opportunities for clinical management of ATL. Integrated omics approaches will further increase our understanding of refractory disease and provide a foundation for designing new treatments that target core molecular drivers.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"289-296"},"PeriodicalIF":4.3,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524652","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":"NF-κB Is a Potential Therapeutic Target for Histone Deacetylase Inhibitor-Resistant Cutaneous T-Cell Lymphoma","authors":"Yuto Takahashi,&nbsp;Akihiro Kitadate,&nbsp;Sayaka Iwama,&nbsp;Wataru Kuroki,&nbsp;Ko Abe,&nbsp;Masahiro Yamada,&nbsp;Sho Ikeda,&nbsp;Hiroyuki Tagawa,&nbsp;Hideki Wakui,&nbsp;Masaki Hikida,&nbsp;Naoto Takahashi","doi":"10.1111/cas.70251","DOIUrl":"10.1111/cas.70251","url":null,"abstract":"<p>Histone deacetylase inhibitors, such as vorinostat, show promise as treatment for T-cell lymphomas including cutaneous T-cell lymphoma. However, the emergence of resistance ultimately leads to disease relapse. To elucidate the underlying mechanisms and identify potential countermeasures, we established histone deacetylase inhibitor-resistant cutaneous T-cell lymphoma cell lines by prolonged exposure to vorinostat. We then comprehensively profiled gene expression in these cell lines by using microarrays and in silico analytical approaches. We identified 83 genes that were significantly upregulated in the resistant cell lines. Subsequent enrichment analyses using ChIP-Atlas and Enrichr revealed that these genes are regulated by particular transcription factors, including RELA/p65, GATA3, and EP300, of which RELA (p65) exhibited the highest composite score. RELA is a key subunit of the NF-κB complex, which is involved in inflammation, cell survival, and proliferation. We demonstrated marked upregulation and nuclear enrichment of p65 and pronounced NF-κB pathway activation in the histone deacetylase inhibitor-resistant cells. The mechanism involved acetylation-mediated inhibition of p65 ubiquitination, which resulted in protein stabilization and enhanced transcriptional activity. Histone deacetylase inhibitor-resistant cell lines displayed heightened sensitivity to inhibition of the NF-κB pathway by bortezomib and dimethyl fumarate. These findings implicate aberrant NF-κB activation as a central driver of the emergence of histone deacetylase inhibitor resistance in cutaneous T-cell lymphoma. Ultimately, our results provide a strong rationale for exploring NF-κB inhibition as a therapeutic strategy to restore or enhance the efficacy of histone deacetylase inhibitor-based therapies, overcome histone deacetylase inhibitor resistance, and improve outcomes for patients with cutaneous T-cell lymphoma.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"407-417"},"PeriodicalIF":4.3,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514465","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":"Overexpression of Transferrin Receptor in Esophageal Squamous Cell Cancer Suggests Poor Prognosis and Potential Therapy","authors":"Naoki Ikenaga,&nbsp;Tsuyoshi Takahashi,&nbsp;Koji Tanaka,&nbsp;Satoshi Serada,&nbsp;Minoru Fujimoto,&nbsp;Kota Momose,&nbsp;Kotaro Yamashita,&nbsp;Tomoki Makino,&nbsp;Takuro Saito,&nbsp;Kazuyoshi Yamamoto,&nbsp;Yukinori Kurokawa,&nbsp;Kiyokazu Nakajima,&nbsp;Tomomi Fujii,&nbsp;Eiichi Morii,&nbsp;Tetsuji Naka,&nbsp;Hidetoshi Eguchi,&nbsp;Yuichiro Doki","doi":"10.1111/cas.70195","DOIUrl":"10.1111/cas.70195","url":null,"abstract":"<p>Despite recent advancements in multimodal therapies for esophageal squamous cell cancer (ESCC), the prognosis remains poor. Identifying suitable biomarkers for predicting prognosis and exploring new therapeutic targets are essential to improving treatment outcomes in ESCC. In this study, we utilized proteomic technology to identify the transferrin receptor (TfR), the main cellular iron importer, as a novel tumor antigen in ESCC. The clinicopathological characteristics of TfR were evaluated by immunohistochemistry using ESCC specimens, revealing that high TfR expression was associated with poor prognosis. Knockdown of TfR in ESCC cell lines resulted in a decrease in intracellular iron levels and suppressed the proliferation of ESCC cell lines, inducing cell cycle arrest in the G0/G1 phase by inhibiting cyclin D, cyclin E, and <i>cyclin-dependent kinase 2</i>. Furthermore, the administration of deferoxamine (DFO), an oral iron chelator, induced a decrease in intracellular iron and suppressed the proliferation of ESCC cell lines and an increase in caspase 3 and 7 activity, indicating the induction of apoptosis. In an ESCC xenograft mouse model, the DFO-treated group exhibited decreased serum iron levels and reduced tumor size. Finally, we confirmed that the deficiency of iron in ESCC cell lines induced an increase in TfR expression via upregulation of iron regulatory protein 2. These findings suggest that TfR is an independent prognostic factor in ESCC and that targeting iron metabolism may be a promising therapeutic approach for improving ESCC treatment outcomes.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 2","pages":"393-406"},"PeriodicalIF":4.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497268","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 Combinatorial Effect of Immune Checkpoint Inhibitors and CD40 Agonistic Antibody in Murine Pancreatic Cancer Model","authors":"Juri Ichikawa,&nbsp;Hiroshi Okuda,&nbsp;Kuniyuki Kawano,&nbsp;Shingo Kato,&nbsp;Shinya Sato,&nbsp;Ryo Kuroishikawa,&nbsp;Daisuke Kurotaki,&nbsp;Wataru Kawase,&nbsp;Haruka Yoshida,&nbsp;Yukihiko Hiroshima,&nbsp;Itaru Endo,&nbsp;Shin Maeda,&nbsp;Tomohiko Tamura","doi":"10.1111/cas.70246","DOIUrl":"10.1111/cas.70246","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all cancer types. Immune checkpoint inhibitors (ICIs) are currently not indicated for patients with PDAC except for those with high microsatellite instability. In this study, we developed an immunocompetent orthotopic transplant mouse model with <i>Kras</i> and <i>Trp53</i> mutations, characterized by high fibrosis and an immunosuppressive tumor microenvironment, closely mimicking human PDAC lesions. This model provides a robust platform for investigating strategies for improving ICI efficacy. We observed that ICI monotherapy yielded minimal efficacy, whereas anti-CD40 agonist antibody (aCD40) monotherapy prolonged survival despite its low impact on primary tumor volume. Moreover, ICIs + aCD40 combination therapy not only extended survival but also significantly reduced tumor burden. These effects were accompanied by enhanced dendritic cell migration to the lymph nodes and T cell priming and activation. Moreover, the expression of immunosuppressive markers in tumor-associated macrophages was decreased. Indeed, gene expression analyses of infiltrating immune cells have revealed a shift in the tumor microenvironment from an immune-tolerant state to an immune-activated state. Our findings suggest that combination therapy with ICIs and aCD40 is a promising treatment strategy for patients with PDAC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"8-18"},"PeriodicalIF":4.3,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490669","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":"Carbonic Anhydrase 12 as a Novel Prognostic Biomarker and Therapeutic Target for High-Risk Follicular Thyroid Carcinoma","authors":"Masashi Tanida,&nbsp;Tsuyoshi Takashima,&nbsp;Shinichiro Tahara,&nbsp;Masaharu Kohara,&nbsp;Haruka Kanai,&nbsp;Masami Suzuki,&nbsp;Motoyuki Suzuki,&nbsp;Mitsuyoshi Hirokawa,&nbsp;Ayana Suzuki,&nbsp;Shinya Sato,&nbsp;Daisuke Okuzaki,&nbsp;Satoshi Nojima,&nbsp;Takahiro Matsui,&nbsp;Hidenori Inohara,&nbsp;Eiichi Morii","doi":"10.1111/cas.70248","DOIUrl":"10.1111/cas.70248","url":null,"abstract":"<p>Follicular thyroid carcinoma is generally associated with a favorable prognosis; however, a subset of follicular thyroid carcinoma shows poor prognosis and frequent distant metastases, and this subset is referred to as high-risk follicular thyroid carcinoma. Difficulty in distinguishing high-risk from low-risk follicular thyroid carcinoma based on current diagnostic approaches leads to the overtreatment of patients with indolent disease. Therefore, the identification of novel biomarkers capable of reliably distinguishing high-risk follicular thyroid carcinoma is essential for accurate risk stratification. Such biomarkers may serve as therapeutic targets for metastatic follicular thyroid carcinoma. This study aimed to identify novel prognostic markers and therapeutic targets for high-risk follicular thyroid carcinoma. In this study, we conducted bulk ribonucleic acid sequencing of high-risk follicular thyroid carcinoma, including widely invasive subtypes and metastatic tumors, and we identified carbonic anhydrase 12 as a candidate biomarker. Immunohistochemical analysis revealed significantly higher carbonic anhydrase 12 expression in follicular thyroid carcinoma than in benign follicular adenomas, particularly in widely invasive and encapsulated angioinvasive subtypes. High carbonic anhydrase 12 expression was an independent predictor of poor disease-free survival, surpassing conventional clinicopathological parameters. Functional assays showed that carbonic anhydrase 12 promoted follicular thyroid carcinoma proliferation, invasion, and migration partly by regulating matrix metalloproteinase 2 expression. Furthermore, carbonic anhydrase 12 inhibitor U104 suppressed follicular thyroid carcinoma cell growth in a dose-dependent manner, and its combination with lenvatinib exerted synergistic antiproliferative effects. Collectively, these findings identified carbonic anhydrase 12 as a novel prognostic biomarker of follicular thyroid carcinoma and a promising therapeutic target.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"257-271"},"PeriodicalIF":4.3,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483016","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":"Prognostic Biomarker of Fertility-Preserving Hormonal Therapy Based on Multigene Panel Testing for Endometrial Cancer","authors":"Takuro Hirano,&nbsp;Kensuke Sakai,&nbsp;Takuma Yoshimura,&nbsp;Tatsuyuki Chiyoda,&nbsp;Kohei Nakamura,&nbsp;Eriko Aimono,&nbsp;Miho Kawaida,&nbsp;Hiroshi Nishihara,&nbsp;Nobuyuki Susumu,&nbsp;Daisuke Aoki,&nbsp;Wataru Yamagami","doi":"10.1111/cas.70240","DOIUrl":"10.1111/cas.70240","url":null,"abstract":"<p>In this study, we identified prognostic biomarkers that predict treatment outcome in patients receiving fertility-preserving high-dose medroxyprogesterone acetate (MPA) therapy through comprehensive multigene panel testing. A total of 38 patients (20 atypical endometrial hyperplasia and 18 stage IA G1 without myometrial invasion) who received first-line MPA therapy were enrolled. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples, and PleSSision-Rapid multigene panel testing was performed. Of the 38 patients, 31 (82%) achieved complete response (CR), 2 (5%) had stable disease (SD), and 5 (13%) had progressive disease (PD) following initial treatment. The median duration to achieve tumor disappearance was 7 months (range: 4–14 months). Following initial treatment, 25 of 32 patients (78%) experienced recurrence, with a median recurrence-free survival (RFS) of 21 months (range: 2–84 months). The most frequently observed actionable gene mutations were <i>PTEN</i> (68.4%), <i>CTNNB1</i> (55.2%), and <i>PIK3CA</i> (33.3%). Patients harboring <i>PTEN</i> mutations in EMG1 required a significantly longer duration to achieve tumor disappearance (<i>p</i> = 0.011). In addition, the presence of <i>PIK3CA</i> mutations in AEH was significantly associated with shorter RFS (<i>p</i> = 0.048). Molecular classification identified 34 patients (89%) with no specific molecular profile (NSMP), 1 patient (3%) with POLE mutation, and 3 patients (8%) with deficient mismatch repair (d-MMR). Most patients undergoing MPA therapy were classified as having NSMP. Genetic alterations, specifically mutations in <i>PTEN</i> and <i>PIK3CA</i>, were significantly associated with treatment outcomes, highlighting their potential as prognostic biomarkers.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"236-245"},"PeriodicalIF":4.3,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483183","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":"Secondary Lower-Body Sarcomas in Cervical Cancer Survivors Following Surgery, Radiotherapy, or Both: A Population-Based Study","authors":"Toshiki Ikawa,&nbsp;Kayo Nakata,&nbsp;Toshitaka Morishima,&nbsp;Ken-ichi Yoshida,&nbsp;Yoshihiro Kuwabara,&nbsp;Mizuki Shimadzu Kato,&nbsp;Yoko Iwaki,&nbsp;Naoyuki Kanayama,&nbsp;Masahiro Morimoto,&nbsp;Koji Konishi,&nbsp;Isao Miyashiro","doi":"10.1111/cas.70229","DOIUrl":"10.1111/cas.70229","url":null,"abstract":"<p>Secondary sarcomas in cervical cancer survivors are understudied. We investigated the incidence and subtypes of secondary sarcomas by treatment modalities, the prognosis of secondary sarcomas, and whether surgery plus radiotherapy increases angiosarcoma incidence. This population-based retrospective cohort study analyzed Osaka Cancer Registry data on women aged 20–84 years diagnosed with cervical cancer (1980–2015), treated with surgery, radiotherapy, or both. Patients with distant metastases, survival time &lt; 1 year, or missing data were excluded. We included 7591 patients with invasive cancer treated with surgery, 3882 with radiotherapy, and 4090 with surgery plus radiotherapy and 13,205 with carcinoma in situ treated with surgery. We assessed the first lower-body sarcoma occurrence ≥ 1 year post-diagnosis. Sarcomas developed in 6 patients treated with surgery (0 angiosarcomas), 10 with radiotherapy (1 angiosarcoma), and 19 with surgery plus radiotherapy (9 angiosarcomas). At 10 years, the cumulative incidence was 0.083% (95% confidence interval [CI], 0.024%–0.24%) for radiotherapy and 0.21% (95% CI, 0.10%–0.41%) for surgery plus radiotherapy, higher than that for surgery (invasive, 0.013%; in situ, 0.028%) (<i>p</i> &lt; 0.001). Angiosarcoma incidence was higher with surgery plus radiotherapy (0.080%; 95% CI, 0.023%–0.23%) than with radiotherapy (0.028%; 95% CI, 0.003%–0.16%) (<i>p</i> = 0.029). Among patients diagnosed with sarcoma after radiotherapy or surgery plus radiotherapy, the 1-year overall survival rate was 33.3% (95% CI, 19.6%–56.8%). Radiotherapy, alone or combined with surgery, increased secondary lower-body sarcoma incidence compared with surgery. To our knowledge, this is the first population-based study to suggest that surgery plus radiotherapy is associated with angiosarcoma in cervical cancer survivors.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"216-225"},"PeriodicalIF":4.3,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483455","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":"MET Enhances Amivantamab Binding to EGFR and Antibody-Dependent Cellular Toxicity","authors":"Shigeki Sato,&nbsp;Neval Yilmaz,&nbsp;Sachiko Arai,&nbsp;Katsuya Sakai,&nbsp;Hiroki Sato,&nbsp;Yuya Murase,&nbsp;Tsukasa Ueda,&nbsp;Hayato Koba,&nbsp;Shigeki Nanjo,&nbsp;Yuichi Tambo,&nbsp;Hiroshi Kotani,&nbsp;Koji Fukuda,&nbsp;Hiroaki Taniguchi,&nbsp;Romain Amyot,&nbsp;Holger Flechsig,&nbsp;Hideko Isozaki,&nbsp;Kunio Matsumoto,&nbsp;Seiji Yano","doi":"10.1111/cas.70228","DOIUrl":"10.1111/cas.70228","url":null,"abstract":"<p>Amivantamab is a bispecific antibody against epidermal growth factor receptor (EGFR) and MET that has been approved for nonsmall cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations and common EGFR mutations, such as exon 19 deletion and L858R. MET has attracted attention as a therapeutic target for lung cancer; however, its role in EGFR binding and amivantamab-induced antibody-dependent cellular toxicity (ADCC) remains unclear. We used high-speed atomic force microscopy (HS-AFM) to observe the real-time binding of amivantamab to the EGFR-extracellular domain (ECD) and MET-ECD and visualized the binding of amivantamab to the EGFR domain 3 and MET Sema domain. Furthermore, we observed the trimer comprising amivantamab bound to EGFR and MET. Western blot analysis of the gel filtration fractions revealed that the MET-ECD enhanced the binding of amivantamab to the EGFR-ECD, which promoted trimer formation. Moreover, amivantamab-induced mononuclear cell-mediated ADCC in NSCLC cells with common EGFR mutations. ADCC activity was positively correlated with EGFR expression in tumor cells. Studies using MET-knockout NSCLC cells revealed that MET enhanced ADCC activity with low concentrations of amivantamab. Thus, MET augments amivantamab binding to EGFR and augments ADCC activity at low amivantamab concentrations. These results indicate that binding to MET contributes to the increased efficacy of amivantamab in NSCLC with common EGFR mutations.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"118-129"},"PeriodicalIF":4.3,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477241","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":"Transforming Growth Factor-β1 as a Biomarker of Malignant Behavior and PD-L1 Expression in Thymic Epithelial Tumors","authors":"Chiaki Nakazono,&nbsp;Satoru Okada,&nbsp;So Tando,&nbsp;Shunta Ishihara,&nbsp;Masanori Shimomura,&nbsp;Tatsuo Furuya,&nbsp;Kenji Kameyama,&nbsp;Stefan Küffer,&nbsp;Denise Müller,&nbsp;Alexander Marx,&nbsp;Satoshi Teramukai,&nbsp;Philipp Ströbel,&nbsp;Kyoko Itoh,&nbsp;Masayoshi Inoue","doi":"10.1111/cas.70243","DOIUrl":"10.1111/cas.70243","url":null,"abstract":"<p>The clinical significance and molecular mechanisms underlying tumor progression in thymic epithelial tumors (TETs) remain largely unclear. In this retrospective single-center study, we evaluated the prognostic value of transforming growth factor-beta 1 (TGF-β1) and its relationship with programmed death-ligand 1 (PD-L1) expression. A total of 92 patients with surgically resected TETs, including 79 thymomas and 13 thymic carcinomas, were included. Immunohistochemical analyses were performed to assess the expression of TGF-β1, PD-L1, phosphorylated Smad2 (pSmad2), and pSmad3. Associations between TGF-β1 expression and clinicopathological features were analyzed, and mechanistic interactions were investigated using two thymic carcinoma cell lines exposed to exogenous TGF-β1. High TGF-β1 expression was observed in 28% of patients and was significantly associated with advanced Masaoka stage (III/IV), shorter tumor doubling time (median 328 vs. 713 days, <i>p</i> = 0.042), and lower 5-year freedom from recurrence (FFR) rates (58.1% vs. 95.1%, <i>p</i> &lt; 0.001, log-rank test). Coexpression of high TGF-β1 and PD-L1 was linked to the poorest prognosis (5-year FFR: 46.1%) and was identified as an independent predictor of recurrence (adjusted hazard ratio: 7.15; 95% confidence interval: 1.20–42.8). Immunohistochemically, TGF-β1 expression positively correlated with PD-L1 and pSmad2/3 expression. In vitro, TGF-β1 stimulation upregulated PD-L1 expression in a dose-dependent manner, accompanied by increased pSmad2/3 activation. These findings indicate that high TGF-β1 expression demarcates a biologically aggressive TET phenotype and, together with PD-L1, refines postoperative risk stratification, while its ability to drive PD-L1 via Smad signaling could support the blockade of these pathways as a potential therapeutic strategy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 1","pages":"181-192"},"PeriodicalIF":4.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472264","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}