Pub Date : 2025-07-01Epub Date: 2025-04-24DOI: 10.1002/cac2.70028
Xianhua Mao, Ka-Shing Cheung, Jing-Tong Tan, Lung-Yi Mak, Chi-Ho Lee, Ho Ming Cheng, Rex Wan-Hin Hui, Esther Wai Yin Chan, Philip Leung-Ho Yu, Man-Fung Yuen, Wai K Leung, Wai-Kay Seto
{"title":"Risk of colorectal cancer and cancer-related mortality in type 2 diabetes patients treated with metformin, SGLT-2 inhibitors, or their combination.","authors":"Xianhua Mao, Ka-Shing Cheung, Jing-Tong Tan, Lung-Yi Mak, Chi-Ho Lee, Ho Ming Cheng, Rex Wan-Hin Hui, Esther Wai Yin Chan, Philip Leung-Ho Yu, Man-Fung Yuen, Wai K Leung, Wai-Kay Seto","doi":"10.1002/cac2.70028","DOIUrl":"10.1002/cac2.70028","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"880-883"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-03-20DOI: 10.1002/cac2.70022
Lea Järke, Saskia Weber-Stiehl, Kensuke Shima, Karlis Arturs Moors, Jerome Genth, Fenja Amrei Schuran, Lena Best, Markus Tschurtschenthaler, Burkhardt Flemer, Silke Lüschen, Christoph Röcken, Andreas Tholey, Christoph Kaleta, Jan Rupp, Philip Rosenstiel, Felix Sommer
{"title":"Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis.","authors":"Lea Järke, Saskia Weber-Stiehl, Kensuke Shima, Karlis Arturs Moors, Jerome Genth, Fenja Amrei Schuran, Lena Best, Markus Tschurtschenthaler, Burkhardt Flemer, Silke Lüschen, Christoph Röcken, Andreas Tholey, Christoph Kaleta, Jan Rupp, Philip Rosenstiel, Felix Sommer","doi":"10.1002/cac2.70022","DOIUrl":"10.1002/cac2.70022","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"722-727"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-03-22DOI: 10.1002/cac2.70008
Xiaoping Cen, Yuanyuan Lan, Jiansheng Zou, Ruilin Chen, Can Hu, Yahan Tong, Chen Zhang, Jingyue Chen, Yuanmei Wang, Run Zhou, Weiwei He, Tianyu Lu, Fred Dubee, Dragomirka Jovic, Wei Dong, Qingqing Gao, Man Ma, Youyong Lu, Yu Xue, Xiangdong Cheng, Yixue Li, Huanming Yang
Advances in multi-omics datasets and analytical methods have revolutionized cancer research, offering a comprehensive, pan-cancer perspective. Pan-cancer studies identify shared mechanisms and unique traits across different cancer types, which are reshaping diagnostic and treatment strategies. However, continued innovation is required to refine these approaches and deepen our understanding of cancer biology and medicine. This review summarized key findings from pan-cancer research and explored their potential to drive future advancements in oncology.
{"title":"Pan-cancer analysis shapes the understanding of cancer biology and medicine.","authors":"Xiaoping Cen, Yuanyuan Lan, Jiansheng Zou, Ruilin Chen, Can Hu, Yahan Tong, Chen Zhang, Jingyue Chen, Yuanmei Wang, Run Zhou, Weiwei He, Tianyu Lu, Fred Dubee, Dragomirka Jovic, Wei Dong, Qingqing Gao, Man Ma, Youyong Lu, Yu Xue, Xiangdong Cheng, Yixue Li, Huanming Yang","doi":"10.1002/cac2.70008","DOIUrl":"10.1002/cac2.70008","url":null,"abstract":"<p><p>Advances in multi-omics datasets and analytical methods have revolutionized cancer research, offering a comprehensive, pan-cancer perspective. Pan-cancer studies identify shared mechanisms and unique traits across different cancer types, which are reshaping diagnostic and treatment strategies. However, continued innovation is required to refine these approaches and deepen our understanding of cancer biology and medicine. This review summarized key findings from pan-cancer research and explored their potential to drive future advancements in oncology.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"728-746"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-11DOI: 10.1002/cac2.70026
Kyoungmin Lee, Kyung-Hun Lee, Dong-Wan Kim, Jeesun Yoon, Yoon Ji Choi, Soohyeon Lee, Ju Won Kim, Kyong Hwa Park, Wonyoung Choi, Youngjoo Lee, Hyewon Ryu, Dong-Hoe Koo, YunGyoo Lee, Hei-Cheul Jeung, Min-Young Lee, Namsu Lee, Myoung Joo Kang, Jieun Lee, Sook Hee Hong, Eun Joo Kang, In Hae Park
{"title":"Phase II study evaluating the safety and efficacy of neratinib and trastuzumab biosimilar in patients with HER2 mutated advanced solid tumors: KCSG AL20-17/KM23 trial.","authors":"Kyoungmin Lee, Kyung-Hun Lee, Dong-Wan Kim, Jeesun Yoon, Yoon Ji Choi, Soohyeon Lee, Ju Won Kim, Kyong Hwa Park, Wonyoung Choi, Youngjoo Lee, Hyewon Ryu, Dong-Hoe Koo, YunGyoo Lee, Hei-Cheul Jeung, Min-Young Lee, Namsu Lee, Myoung Joo Kang, Jieun Lee, Sook Hee Hong, Eun Joo Kang, In Hae Park","doi":"10.1002/cac2.70026","DOIUrl":"10.1002/cac2.70026","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"841-845"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-10DOI: 10.1002/cac2.70025
Xiangyi Kong, Xintong Xie, Juan Wu, Xiangyu Wang, Wenxiang Zhang, Shuowen Wang, Daria Valerievna Abbasova, Yi Fang, Hongnan Jiang, Jidong Gao, Jing Wang
Cancer immunotherapy offers renewed hope for treating this disease. However, cancer cells possess inherent mechanisms that enable them to circumvent each stage of the immune cycle, thereby evading anti-cancer immunity and leading to resistance. Various functionalized nanoparticles (NPs), modified with cationic lipids, pH-sensitive compounds, or photosensitizers, exhibit unique physicochemical properties that facilitate the targeted delivery of therapeutic agents to cancer cells or the tumor microenvironment (TME). These NPs are engineered to modify immune activity. The crucial signal transduction pathways and mechanisms by which functionalized NPs counteract immunotherapy resistance are outlined, including enhancing antigen presentation, boosting the activation and infiltration of tumor-specific immune cells, inducing immunogenic cell death, and counteracting immunosuppressive conditions in the TME. Additionally, this review summarizes current clinical trials involving NP-based immunotherapy. Ultimately, it highlights the potential of nanotechnology to advance cancer immunotherapy.
{"title":"Combating cancer immunotherapy resistance: a nano-medicine perspective.","authors":"Xiangyi Kong, Xintong Xie, Juan Wu, Xiangyu Wang, Wenxiang Zhang, Shuowen Wang, Daria Valerievna Abbasova, Yi Fang, Hongnan Jiang, Jidong Gao, Jing Wang","doi":"10.1002/cac2.70025","DOIUrl":"10.1002/cac2.70025","url":null,"abstract":"<p><p>Cancer immunotherapy offers renewed hope for treating this disease. However, cancer cells possess inherent mechanisms that enable them to circumvent each stage of the immune cycle, thereby evading anti-cancer immunity and leading to resistance. Various functionalized nanoparticles (NPs), modified with cationic lipids, pH-sensitive compounds, or photosensitizers, exhibit unique physicochemical properties that facilitate the targeted delivery of therapeutic agents to cancer cells or the tumor microenvironment (TME). These NPs are engineered to modify immune activity. The crucial signal transduction pathways and mechanisms by which functionalized NPs counteract immunotherapy resistance are outlined, including enhancing antigen presentation, boosting the activation and infiltration of tumor-specific immune cells, inducing immunogenic cell death, and counteracting immunosuppressive conditions in the TME. Additionally, this review summarizes current clinical trials involving NP-based immunotherapy. Ultimately, it highlights the potential of nanotechnology to advance cancer immunotherapy.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"813-840"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Tumor-associated neutrophils (TANs) play a critical role in modulating immune responses and exhibit significant heterogeneity. Our previous study demonstrated that jagged canonical Notch ligand 2 (JAG2)+ TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC), but the underlying mechanism remains unclear. This study aimed to elucidate the role of JAG2+ TANs in tumor immunosuppressive microenvironment in HGSOC.
Methods: HGSOC samples were collected, with 274 samples constituting two independent cohorts (training and validation cohorts) and an additional 30 samples utilized to establish patient-derived tumor organoids (PDTOs). We characterized the number and phenotype of JAG2+ TANs by multiplex immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq). We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems, flow cytometry, tumor-bearing mouse models, and PDTOs.
Results: JAG2+ TANs expressed elevated levels of immunosuppressive molecules, including programmed cell death ligand 1 and CD14, and had independent prognostic value for the overall survival of patients with HGSOC. scRNA-seq analysis revealed that JAG2+ TANs exhibited a terminally mature phenotype. The infiltration of JAG2+ TANs was positively correlated with the abundance of effector regulatory T cells (eTregs). Interaction with JAG2+ TANs skewed CD4+ T cells towards an eTreg phenotype, a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2. Furthermore, we demonstrated that JAG2+ TANs enhanced Notch signaling activation, ultimately promoting recombination signal binding protein for immunoglobulin kappa J region (RBPJ)-induced differentiation of naïve CD4+ T cells into eTregs. Clinically, JAG2+ TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs) in both xenograft and PDTO models.
Conclusions: The emergence of JAG2+ TANs is crucial for the differentiation of eTregs, which triggers immune evasion and resistance to anti-PD-1 therapy. Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.
{"title":"Immunosuppressive JAG2<sup>+</sup> tumor-associated neutrophils hamper PD-1 blockade response in ovarian cancer by mediating the differentiation of effector regulatory T cells.","authors":"Chenyang Wang, Moran Yang, Yujing Zhong, Kankan Cao, Xueling Wang, Chen Zhang, Yiying Wang, Mengdi He, Jiaqi Lu, Guodong Zhang, Yan Huang, Haiou Liu","doi":"10.1002/cac2.70021","DOIUrl":"10.1002/cac2.70021","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated neutrophils (TANs) play a critical role in modulating immune responses and exhibit significant heterogeneity. Our previous study demonstrated that jagged canonical Notch ligand 2 (JAG2)<sup>+</sup> TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC), but the underlying mechanism remains unclear. This study aimed to elucidate the role of JAG2<sup>+</sup> TANs in tumor immunosuppressive microenvironment in HGSOC.</p><p><strong>Methods: </strong>HGSOC samples were collected, with 274 samples constituting two independent cohorts (training and validation cohorts) and an additional 30 samples utilized to establish patient-derived tumor organoids (PDTOs). We characterized the number and phenotype of JAG2<sup>+</sup> TANs by multiplex immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq). We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems, flow cytometry, tumor-bearing mouse models, and PDTOs.</p><p><strong>Results: </strong>JAG2<sup>+</sup> TANs expressed elevated levels of immunosuppressive molecules, including programmed cell death ligand 1 and CD14, and had independent prognostic value for the overall survival of patients with HGSOC. scRNA-seq analysis revealed that JAG2<sup>+</sup> TANs exhibited a terminally mature phenotype. The infiltration of JAG2<sup>+</sup> TANs was positively correlated with the abundance of effector regulatory T cells (eTregs). Interaction with JAG2<sup>+</sup> TANs skewed CD4<sup>+</sup> T cells towards an eTreg phenotype, a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2. Furthermore, we demonstrated that JAG2<sup>+</sup> TANs enhanced Notch signaling activation, ultimately promoting recombination signal binding protein for immunoglobulin kappa J region (RBPJ)-induced differentiation of naïve CD4<sup>+</sup> T cells into eTregs. Clinically, JAG2<sup>+</sup> TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs) in both xenograft and PDTO models.</p><p><strong>Conclusions: </strong>The emergence of JAG2<sup>+</sup> TANs is crucial for the differentiation of eTregs, which triggers immune evasion and resistance to anti-PD-1 therapy. Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"747-773"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seungbyn Baek, Junha Cha, Min Hee Hong, Gamin Kim, Yoon Woo Koh, Dahee Kim, Wonrak Son, Chan-Young Ock, Seungeun Lee, Martin Hemberg, Seong Yong Park, Hye Ryun Kim, Insuk Lee
<p>Esophageal cancer comprises 2 anatomically shared but histologically different subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous bulk-level genomic and clinical studies have shown that ESCC shares molecular features with head and neck squamous cell carcinoma (HNSCC) [<span>1</span>] and is generally more responsive to immune checkpoint blockade (ICB) therapies than EAC [<span>2</span>], which is similar to gastric adenocarcinoma (GAC) [<span>1</span>]. Recent clinical trials have further demonstrated clinical benefits from various ICB therapies, including combination approaches, for ESCC [<span>3</span>].</p><p>To further expand the comparison at single-cell resolution of tumor microenvironment (TME), we conducted single-cell transcriptomic analysis on tumors from 35 patients representing 4 cancer types located near the esophagus: ESCC, EAC, HNSCC, and GAC (Supplementary Materials and Methods). By integrating newly generated single-cell datasets with published datasets (Supplementary Table S1) [<span>4, 5</span>], we analyzed more than 200,000 cells within TME (Supplementary Figure S1, Supplementary Figure S2A-C, Supplementary Table S2). This high-resolution approach allowed the dissection of cellular heterogeneity of malignant cells and various immune components within the TME (Figure 1A).</p><p>Differentially expressed gene (DEG) analysis of malignant cells revealed a clear separation based on epithelial cell origin (Supplementary Figure S2D). For detailed cancer cell states, we generated 14 malignant metaprograms (MPs) using non-negative matrix factorization (Supplementary Table S3). Histology-specific MPs, representing squamous or glandular differentiation, dominated the expression landscape, while additional MPs distinguished tumor types based on cell cycle dynamics, endocrine-like features, and activation of Aldo-keto reductase family 1 (AKR1) family genes, thereby providing insights into diverse and shared oncogenic processes (Figure 1B). Furthermore, we generated MPs from immune and stromal compartments and calculated correlations among them (Supplementary Figure S2E, Supplementary Table S3). We identified clusters of coordinated MPs, including an “immune activating” cluster characterized by interferon signaling and activation of adaptive immunity, predominantly enriched in HNSCC and ESCC. In contrast, heat-shock protein (HSP) MP, negatively correlated with the immune activating cluster, was more common in EAC and GAC, suggesting potentially immunosuppressive TMEs.</p><p>To better understand the immune compartments of the TME, we conducted in-depth analyses of each major immune cell type using subclustering approaches. We first focused on CD8<sup>+</sup> T cells for their roles in anti-tumor immunity. We identified several key subtypes including naive/memory, effector, stress-response (HSP high), and exhausted populations (Supplementary Figure S3A-B, Supplementary Table S4). For exhausted
{"title":"Comparative single-cell analysis of esophageal cancer subtypes reveals tumor microenvironment distinctions explaining varied immunotherapy responses","authors":"Seungbyn Baek, Junha Cha, Min Hee Hong, Gamin Kim, Yoon Woo Koh, Dahee Kim, Wonrak Son, Chan-Young Ock, Seungeun Lee, Martin Hemberg, Seong Yong Park, Hye Ryun Kim, Insuk Lee","doi":"10.1002/cac2.70046","DOIUrl":"10.1002/cac2.70046","url":null,"abstract":"<p>Esophageal cancer comprises 2 anatomically shared but histologically different subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous bulk-level genomic and clinical studies have shown that ESCC shares molecular features with head and neck squamous cell carcinoma (HNSCC) [<span>1</span>] and is generally more responsive to immune checkpoint blockade (ICB) therapies than EAC [<span>2</span>], which is similar to gastric adenocarcinoma (GAC) [<span>1</span>]. Recent clinical trials have further demonstrated clinical benefits from various ICB therapies, including combination approaches, for ESCC [<span>3</span>].</p><p>To further expand the comparison at single-cell resolution of tumor microenvironment (TME), we conducted single-cell transcriptomic analysis on tumors from 35 patients representing 4 cancer types located near the esophagus: ESCC, EAC, HNSCC, and GAC (Supplementary Materials and Methods). By integrating newly generated single-cell datasets with published datasets (Supplementary Table S1) [<span>4, 5</span>], we analyzed more than 200,000 cells within TME (Supplementary Figure S1, Supplementary Figure S2A-C, Supplementary Table S2). This high-resolution approach allowed the dissection of cellular heterogeneity of malignant cells and various immune components within the TME (Figure 1A).</p><p>Differentially expressed gene (DEG) analysis of malignant cells revealed a clear separation based on epithelial cell origin (Supplementary Figure S2D). For detailed cancer cell states, we generated 14 malignant metaprograms (MPs) using non-negative matrix factorization (Supplementary Table S3). Histology-specific MPs, representing squamous or glandular differentiation, dominated the expression landscape, while additional MPs distinguished tumor types based on cell cycle dynamics, endocrine-like features, and activation of Aldo-keto reductase family 1 (AKR1) family genes, thereby providing insights into diverse and shared oncogenic processes (Figure 1B). Furthermore, we generated MPs from immune and stromal compartments and calculated correlations among them (Supplementary Figure S2E, Supplementary Table S3). We identified clusters of coordinated MPs, including an “immune activating” cluster characterized by interferon signaling and activation of adaptive immunity, predominantly enriched in HNSCC and ESCC. In contrast, heat-shock protein (HSP) MP, negatively correlated with the immune activating cluster, was more common in EAC and GAC, suggesting potentially immunosuppressive TMEs.</p><p>To better understand the immune compartments of the TME, we conducted in-depth analyses of each major immune cell type using subclustering approaches. We first focused on CD8<sup>+</sup> T cells for their roles in anti-tumor immunity. We identified several key subtypes including naive/memory, effector, stress-response (HSP high), and exhausted populations (Supplementary Figure S3A-B, Supplementary Table S4). For exhausted","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1194-1199"},"PeriodicalIF":24.9,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jin-Seong Hwang, Sugi Lee, Gyeonghwa Kim, Hoibin Jeong, Kiyoon Kwon, Eunsun Jung, Yuna Roh, Taesang Son, Hana Lee, Moo-Seung Lee, Kyoung-Jin Oh, Hye Won Lee, Yu Rim Lee, Soo Young Park, Won Young Tak, Hyun Seung Ban, Hyun-Soo Cho, Mi-Young Son, Jang-Seong Kim, Keun Hur, Dae-Soo Kim, Tae-Su Han
<p>Hepatocellular carcinoma (HCC) is a critical cancer worldwide due to its low survival rate [<span>1</span>]. In the United States, the overall 5-year survival rate of patients with HCC is 22%, which decreases sharply with cancer progression [<span>2</span>]. Early detection of HCC improves patient survival. Serum alpha-fetoprotein (AFP) is a widely used biomarker for the diagnosis of HCC, but it is often elevated in patients with cirrhosis, resulting in false-positive results [<span>3</span>]. Diagnostic markers for early detection of HCC have been investigated previously [<span>4</span>], but none are widely applied in clinical settings. HCC pathogenesis is closely associated with hepatitis B and C virus (HBV and HCV) infections, which induce chronic inflammation, leading to cirrhosis and elevating the risk of malignant transformation [<span>5</span>]. Environmental and lifestyle factors, such as diet and alcohol consumption, drive the progression from steatosis to fibrosis, cirrhosis, and eventually HCC [<span>6</span>]. Due to HCC's multifactorial etiology and prolonged progression, identifying early diagnostic biomarkers remains a challenge [<span>7</span>]. Thus, integrating analyses of both pre-HCC and cancerous samples is essential for developing robust early detection strategies. This study aimed to: (1) establish stepwise animal models for HCC-related conditions including non-alcoholic steatohepatitis (NASH) and fibrosis [<span>8</span>]; (2) identify exosomal microRNA (exo-miRNA) signatures for early HCC diagnosis; and (3) develop and validate an artificial intelligence (AI)-based multi-marker model combining exo-miRNAs and AFP levels for accurate HCC diagnosis using clinical samples (Supplementary Figure S1, Supplementary Materials and Methods).</p><p>Initially, stepwise mouse models of liver diseases were developed (Figure 1A-C, Supplementary Figure S2A-B). Highly similar gene expression patterns between mouse and human liver diseases were discovered using transcriptome analysis of liver tissues and comparison with public databases (Supplementary Figure S2C). The serum exosomes were then isolated and characterized (Figure 1D, Supplementary Figure S2D), followed by exo-miRNA profiling using Nanostring analysis. This profiling was conducted on mouse models of liver diseases and human samples, which included healthy individuals (<i>n</i> = 7), patients with cirrhosis (<i>n</i> = 6), and patients with HCC (<i>n</i> = 18) (profiling set; Supplementary Table S1).</p><p>The selection criteria for exo-miRNAs included the upregulation of exo-miRNAs in serum exosomes from mice or humans with liver diseases compared with levels in exosomes from normal mice or healthy controls. Four exo-miRNAs were upregulated in samples from mice or humans with HCC compared with those from normal mice or healthy controls. Subsequently, additional criteria were applied to distinguish between cirrhosis and HCC using the mouse model, resulting in 4 additional ex
{"title":"A serum exosomal microRNA-based artificial intelligence diagnostic model for highly accurate detection of hepatocellular carcinoma","authors":"Jin-Seong Hwang, Sugi Lee, Gyeonghwa Kim, Hoibin Jeong, Kiyoon Kwon, Eunsun Jung, Yuna Roh, Taesang Son, Hana Lee, Moo-Seung Lee, Kyoung-Jin Oh, Hye Won Lee, Yu Rim Lee, Soo Young Park, Won Young Tak, Hyun Seung Ban, Hyun-Soo Cho, Mi-Young Son, Jang-Seong Kim, Keun Hur, Dae-Soo Kim, Tae-Su Han","doi":"10.1002/cac2.70043","DOIUrl":"10.1002/cac2.70043","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a critical cancer worldwide due to its low survival rate [<span>1</span>]. In the United States, the overall 5-year survival rate of patients with HCC is 22%, which decreases sharply with cancer progression [<span>2</span>]. Early detection of HCC improves patient survival. Serum alpha-fetoprotein (AFP) is a widely used biomarker for the diagnosis of HCC, but it is often elevated in patients with cirrhosis, resulting in false-positive results [<span>3</span>]. Diagnostic markers for early detection of HCC have been investigated previously [<span>4</span>], but none are widely applied in clinical settings. HCC pathogenesis is closely associated with hepatitis B and C virus (HBV and HCV) infections, which induce chronic inflammation, leading to cirrhosis and elevating the risk of malignant transformation [<span>5</span>]. Environmental and lifestyle factors, such as diet and alcohol consumption, drive the progression from steatosis to fibrosis, cirrhosis, and eventually HCC [<span>6</span>]. Due to HCC's multifactorial etiology and prolonged progression, identifying early diagnostic biomarkers remains a challenge [<span>7</span>]. Thus, integrating analyses of both pre-HCC and cancerous samples is essential for developing robust early detection strategies. This study aimed to: (1) establish stepwise animal models for HCC-related conditions including non-alcoholic steatohepatitis (NASH) and fibrosis [<span>8</span>]; (2) identify exosomal microRNA (exo-miRNA) signatures for early HCC diagnosis; and (3) develop and validate an artificial intelligence (AI)-based multi-marker model combining exo-miRNAs and AFP levels for accurate HCC diagnosis using clinical samples (Supplementary Figure S1, Supplementary Materials and Methods).</p><p>Initially, stepwise mouse models of liver diseases were developed (Figure 1A-C, Supplementary Figure S2A-B). Highly similar gene expression patterns between mouse and human liver diseases were discovered using transcriptome analysis of liver tissues and comparison with public databases (Supplementary Figure S2C). The serum exosomes were then isolated and characterized (Figure 1D, Supplementary Figure S2D), followed by exo-miRNA profiling using Nanostring analysis. This profiling was conducted on mouse models of liver diseases and human samples, which included healthy individuals (<i>n</i> = 7), patients with cirrhosis (<i>n</i> = 6), and patients with HCC (<i>n</i> = 18) (profiling set; Supplementary Table S1).</p><p>The selection criteria for exo-miRNAs included the upregulation of exo-miRNAs in serum exosomes from mice or humans with liver diseases compared with levels in exosomes from normal mice or healthy controls. Four exo-miRNAs were upregulated in samples from mice or humans with HCC compared with those from normal mice or healthy controls. Subsequently, additional criteria were applied to distinguish between cirrhosis and HCC using the mouse model, resulting in 4 additional ex","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1188-1193"},"PeriodicalIF":24.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katia Mariniello, James F. H. Pittaway, Barbara Altieri, Kleiton Silva Borges, Irene Hadjidemetriou, Claudio Ribeiro, Gerard Ruiz-Babot, David S. Tourigny, Jiang A. Lim, Julie Foster, Julie Cleaver, Jane Sosabowski, Nafis Rahman, Milena Doroszko, Constanze Hantel, Sandra Sigala, Andrea Abate, Mariangela Tamburello, Katja Kiseljak-Vassiliades, Margaret Wierman, Charlotte Hall, Laila Parvanta, Tarek E. Abdel-Aziz, Teng-Teng Chung, Aimee Di Marco, Fausto Palazzo, Celso E. Gomez-Sanchez, David R. Taylor, Oliver Rayner, Cristina L. Ronchi, Carles Gaston-Massuet, Silviu Sbiera, William M. Drake, Emanuel Rognoni, Matthias Kroiss, David T. Breault, Martin Fassnacht, Leonardo Guasti
The cover image is based on the article Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma by James Pittaway et al., https://doi.org/10.1002/cac2.70012.
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N-acetyltransferase 10 (NAT10) was reported to be associated with the immune microenvironment in several cancers. However, it is not known in pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the roles and mechanisms of NAT10 in tumor malignancy and the tumor microenvironment (TME) in PDAC.
Methods
NAT10 expression and its role in tumor progression and clinical prognosis were analyzed using bioinformatics and functional assays. Downstream genes regulated by NAT10 and their underlying mechanisms were explored using acetylated RNA immunoprecipitation, quantitative polymerase chain reaction, RNA immunoprecipitation, and Western blotting. The role and mechanism of NAT10 in the PDAC TME were further explored using bioinformatics, single-cell RNA sequencing, multiplexed immunofluorescence, and flow cytometry. The association between NAT10 and immunotherapeutic response was investigated in a mouse model by inhibiting the programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) axis with a PD-1/PD-L1 binding inhibitor, Naamidine J.
Results
NAT10 was upregulated in PDAC tissues and cell lines, and was associated with poor progression-free survival of PDAC patients. NAT10 promoted tumor progression by enhancing the mRNA stability of laminin β3 (LAMB3) via N4-acetylation modification, thereby activating the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pathway. NAT10 promoted subcutaneous tumor growth, increased the proportion of exhausted CD8+ T cells (CD8+ Tex), especially the intermediate CD8+ Tex subset, and decreased the proportion of cytotoxic CD8+ T cell (CD8+ Tc) subset in the PDAC TME. Naamidine J treatment significantly enhanced the proportion of CD8+ Tc subset and reduced the proportion of intermediate CD8+ Tex subset in mice bearing subcutaneous tumors with high NAT10 expression. Regarding the regulatory mechanism, NAT10 increased PD-L1 expression and abundance in tumor cells by activating the LAMB3/FAK/ERK pathway, thereby reducing the cytotoxicity of CD8+ T cells. Inhibition of the PD-1/PD-L1 axis with Naamidine J retrieved CD8+ T cell cytotoxicity.
Conclusions
This study proposes a regulatory role of NAT10 in tumor progression and immune microenvironment via the LAMB3/FAK/ERK pathway in PDAC. These findings may favor the selection of cand
{"title":"NAT10 regulates tumor progression and immune microenvironment in pancreatic ductal adenocarcinoma via the N4-acetylated LAMB3-mediated FAK/ERK pathway","authors":"Enhong Chen, Qin Wang, Leisheng Wang, Zebo Huang, Dongjie Yang, Changyong Zhao, Wuqiang Chen, Shuo Zhang, Shuming Xiong, Youzhao He, Yong Mao, Hao Hu","doi":"10.1002/cac2.70045","DOIUrl":"10.1002/cac2.70045","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>N-acetyltransferase 10 (NAT10) was reported to be associated with the immune microenvironment in several cancers. However, it is not known in pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the roles and mechanisms of NAT10 in tumor malignancy and the tumor microenvironment (TME) in PDAC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>NAT10 expression and its role in tumor progression and clinical prognosis were analyzed using bioinformatics and functional assays. Downstream genes regulated by NAT10 and their underlying mechanisms were explored using acetylated RNA immunoprecipitation, quantitative polymerase chain reaction, RNA immunoprecipitation, and Western blotting. The role and mechanism of NAT10 in the PDAC TME were further explored using bioinformatics, single-cell RNA sequencing, multiplexed immunofluorescence, and flow cytometry. The association between NAT10 and immunotherapeutic response was investigated in a mouse model by inhibiting the programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) axis with a PD-1/PD-L1 binding inhibitor, Naamidine J.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NAT10 was upregulated in PDAC tissues and cell lines, and was associated with poor progression-free survival of PDAC patients. NAT10 promoted tumor progression by enhancing the mRNA stability of laminin β3 (LAMB3) via N4-acetylation modification, thereby activating the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pathway. NAT10 promoted subcutaneous tumor growth, increased the proportion of exhausted CD8<sup>+</sup> T cells (CD8<sup>+</sup> Tex), especially the intermediate CD8<sup>+</sup> Tex subset, and decreased the proportion of cytotoxic CD8<sup>+</sup> T cell (CD8<sup>+</sup> Tc) subset in the PDAC TME. Naamidine J treatment significantly enhanced the proportion of CD8<sup>+</sup> Tc subset and reduced the proportion of intermediate CD8<sup>+</sup> Tex subset in mice bearing subcutaneous tumors with high NAT10 expression. Regarding the regulatory mechanism, NAT10 increased PD-L1 expression and abundance in tumor cells by activating the LAMB3/FAK/ERK pathway, thereby reducing the cytotoxicity of CD8<sup>+</sup> T cells. Inhibition of the PD-1/PD-L1 axis with Naamidine J retrieved CD8<sup>+</sup> T cell cytotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study proposes a regulatory role of NAT10 in tumor progression and immune microenvironment via the LAMB3/FAK/ERK pathway in PDAC. These findings may favor the selection of cand","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":"1162-1187"},"PeriodicalIF":24.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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