Pub Date : 2026-03-24DOI: 10.1158/0008-5472.can-25-4018
Laura Alvaro-Espinosa,Angel Marquez-Galera,Neibla Priego,Virginia García-Calvo,Maria Perea-García,Carolina Hernandez-Oliver,Diana Retana,Oliva Sanchez,Ana de Pablos-Aragoneses,Pedro García-Gómez,Osvaldo Graña-Castro,Óscar Lapuente-Santana,Laura Serrano-Ron,Fatima Al-Shahrour,Ana Cayuela López,Isabel Peset,Diego Megías,Mihaela Ola,Damir Varešlija,Leonie S Young,Yolanda Martí-Mateos,Jose A Enríquez,Elena Hernández-Encinas,Carmen Blanco-Aparicio,Maria S Soengas,Juergen Bernhagen,Alejandro Antón-Fernández,Jesús Ávila,Miguel A Marchena,Maximiliano Torres,Fernando de Castro,Mar Márquez-Ropero,Amanda Sierra,Jose P Lopez-Atalaya,Renacer Group,Manuel Valiente,Patricia Baena Galán,Cecilia Sobrino,Inmaculada Almenara,Daniel Alba-Olano,Carmen Ortega-Sabater,María-Jesús Artiga,Eva Ortega-Paino,Ana González Piñeiro,Concepción Fiaño Valverde,Adolfo de la Lama Zaragoza,Alejandra Londoño Quiroz,Pedro David Delgado López,Mar Pascual-Llorente,Ángela Díaz-Piqueras,Ángel Amador Arriaga Aragón,Syonghyun Nam-Cha,Cristina Barrena-López,Gerard Plans Ahicart,Begoña Escolano Otín,Isabel Gil Aldea,Juan Delgado-Fernández,Juan M Sepúlveda-Sánchez,Angel Perez-Nuñez,Aurelio Hernández-Laín,Oscar Toldos González,Ricardo Gargini,Denisse Alcivar,José A Fernández Alén,Guillermo Blasco García de Andoain,Santiago Cepeda Chafla,Elena Martínez Zamorano,Manuela Mollejo Villanueva,Maria-Sonsoles Opazo Rodríguez,Ángel Rodriguez de Lope Llorca,María Arbaiza Martínez,Gonzalo M Múzquiz Rueda,Sergi Benavente,Fran Martínez-Ricarte,Santiago Ramón Y Cajal,Marta Sesé Faustino,Laura Fernández Cabré,Javier Hernández-Losa,Elena Martínez-Saez,Lourdes Calero Félix,Kelly Vargas-Osorio
The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. Here, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon gamma in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand MIF that bound the CD74 receptor and induced its translocation to the nucleus where it activated a NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, while it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease non-canonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.
{"title":"MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and are Clinically Relevant Across Central Nervous System Disorders.","authors":"Laura Alvaro-Espinosa,Angel Marquez-Galera,Neibla Priego,Virginia García-Calvo,Maria Perea-García,Carolina Hernandez-Oliver,Diana Retana,Oliva Sanchez,Ana de Pablos-Aragoneses,Pedro García-Gómez,Osvaldo Graña-Castro,Óscar Lapuente-Santana,Laura Serrano-Ron,Fatima Al-Shahrour,Ana Cayuela López,Isabel Peset,Diego Megías,Mihaela Ola,Damir Varešlija,Leonie S Young,Yolanda Martí-Mateos,Jose A Enríquez,Elena Hernández-Encinas,Carmen Blanco-Aparicio,Maria S Soengas,Juergen Bernhagen,Alejandro Antón-Fernández,Jesús Ávila,Miguel A Marchena,Maximiliano Torres,Fernando de Castro,Mar Márquez-Ropero,Amanda Sierra,Jose P Lopez-Atalaya,Renacer Group,Manuel Valiente,Patricia Baena Galán,Cecilia Sobrino,Inmaculada Almenara,Daniel Alba-Olano,Carmen Ortega-Sabater,María-Jesús Artiga,Eva Ortega-Paino,Ana González Piñeiro,Concepción Fiaño Valverde,Adolfo de la Lama Zaragoza,Alejandra Londoño Quiroz,Pedro David Delgado López,Mar Pascual-Llorente,Ángela Díaz-Piqueras,Ángel Amador Arriaga Aragón,Syonghyun Nam-Cha,Cristina Barrena-López,Gerard Plans Ahicart,Begoña Escolano Otín,Isabel Gil Aldea,Juan Delgado-Fernández,Juan M Sepúlveda-Sánchez,Angel Perez-Nuñez,Aurelio Hernández-Laín,Oscar Toldos González,Ricardo Gargini,Denisse Alcivar,José A Fernández Alén,Guillermo Blasco García de Andoain,Santiago Cepeda Chafla,Elena Martínez Zamorano,Manuela Mollejo Villanueva,Maria-Sonsoles Opazo Rodríguez,Ángel Rodriguez de Lope Llorca,María Arbaiza Martínez,Gonzalo M Múzquiz Rueda,Sergi Benavente,Fran Martínez-Ricarte,Santiago Ramón Y Cajal,Marta Sesé Faustino,Laura Fernández Cabré,Javier Hernández-Losa,Elena Martínez-Saez,Lourdes Calero Félix,Kelly Vargas-Osorio","doi":"10.1158/0008-5472.can-25-4018","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-4018","url":null,"abstract":"The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. Here, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon gamma in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand MIF that bound the CD74 receptor and induced its translocation to the nucleus where it activated a NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, while it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease non-canonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a frontline tyrosine kinase inhibitor. Resistance arises from heterogeneous mechanisms involving metabolic reprogramming and mitochondrial adaptation, implicating regulators of these processes as potential therapeutic targets. Here, we identified α/β hydrolase domain containing 6 (ABHD6) as a critical driver of lenvatinib resistance by perturbing mitochondrial dynamics. Ligand-binding at the S148 catalytic site allosterically controlled a molecular switch between canonical enzymatic and non-canonical scaffolding functions of ABHD6, and the pro-resistance function was independent of catalysis but required an unoccupied catalytic site. In resistant HCC, the Warburg effect elevated lactate, leading to K245 lactylation of ABHD6. This modification triggered the mitochondrial translocation of ABHD6, where it functioned as a scaffold that competitively bound the fission regulator FIS1 and displaced DRP1. Disruption of the fission machinery stabilized hyperfused mitochondria, thereby conferring lenvatinib resistance by suppressing drug-induced apoptosis and ROS generation. Both inhibiting lactate production and enforcing occupancy of the S148 site with substrates or a specific inhibitor blocked formation of the ABHD6-FIS1 complex, reactivated mitochondrial fission, and restored lenvatinib sensitivity. This study identified a lactate-driven functional switch in ABHD6 and established that targeting this allosteric mechanism is an effective therapeutic strategy to overcome lenvatinib resistance.
{"title":"Lactylation Converts ABHD6 into a Mitochondrial Regulator that Drives Lenvatinib Resistance in Hepatocellular Carcinoma.","authors":"Yuening Sun,Chengju Luo,Hui Yang,Jiaxin Ye,Fengliang Song,Quanhua Yi,Wenhao Zou,Yan Huang,Xiangjun Fan,Lei Wang,Yanan Zhang,Qian Ding,Yizhun Zhu,Zhiyuan Tang","doi":"10.1158/0008-5472.can-25-4282","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-4282","url":null,"abstract":"Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a frontline tyrosine kinase inhibitor. Resistance arises from heterogeneous mechanisms involving metabolic reprogramming and mitochondrial adaptation, implicating regulators of these processes as potential therapeutic targets. Here, we identified α/β hydrolase domain containing 6 (ABHD6) as a critical driver of lenvatinib resistance by perturbing mitochondrial dynamics. Ligand-binding at the S148 catalytic site allosterically controlled a molecular switch between canonical enzymatic and non-canonical scaffolding functions of ABHD6, and the pro-resistance function was independent of catalysis but required an unoccupied catalytic site. In resistant HCC, the Warburg effect elevated lactate, leading to K245 lactylation of ABHD6. This modification triggered the mitochondrial translocation of ABHD6, where it functioned as a scaffold that competitively bound the fission regulator FIS1 and displaced DRP1. Disruption of the fission machinery stabilized hyperfused mitochondria, thereby conferring lenvatinib resistance by suppressing drug-induced apoptosis and ROS generation. Both inhibiting lactate production and enforcing occupancy of the S148 site with substrates or a specific inhibitor blocked formation of the ABHD6-FIS1 complex, reactivated mitochondrial fission, and restored lenvatinib sensitivity. This study identified a lactate-driven functional switch in ABHD6 and established that targeting this allosteric mechanism is an effective therapeutic strategy to overcome lenvatinib resistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-20DOI: 10.1158/0008-5472.can-25-3776
Tito A Sandoval,Yize Li,Naoshad Muhammad,Tresha Desai,Reyka G Jayasinghe,Saman Zeeshan,Kay Jayachandran,Matthew J Inkman,Michael R Waters,Eliwaza Naomi S Msengi,Tyler R McKinnish,Ibrahim Hatipoglu,Ana Carolina Paschoalini Mafra,Muyassar Anwar,Donghua Hu,Dhaval P Bhatt,Varintra E Lander,R Jay Mashl,Andrew Houston,Liyun Chen,Jessika Contreras,Clifford G Robinson,Sherri R Davies,Julie Belmar,Shunqiang Li,Michael B Major,David G DeNardo,Stephanie Markovina,Brian T Edelson,Jin Zhang,Li Ding,Julie K Schwarz
Despite advances in screening and prevention, cervical cancer remains a leading cause of cancer-related deaths worldwide, underscoring the need for better treatments. In this study, we conducted a multicohort longitudinal study of human cervical tumors and the tumor microenvironment during chemoradiotherapy (CRT) and integrated RNA sequencing and single-cell transcriptomics to define the cellular and molecular programs shaping cell interactions and how CRT alters them. The analysis identified multiple therapeutic targets in CRT-resistant tumors, notably including MDM2, a key mediator of radiation responses in tumor and immune cells. MDM2 inhibition enhanced the effects of radiotherapy in human papillomavirus (HPV)-positive, TP53 wild-type cervical cancer cells; improved radiation response; and reshaped the immune landscape in preclinical models. These findings highlight the potential of combining MDM2 inhibition with CRT to overcome resistance and improve patient outcomes. The insights into therapy-induced changes in tumor and immune compartments could guide improved strategies against treatment-resistant HPV-positive cancers.SIGNIFICANCEMapping of the impact of chemoradiation on cellular interactions in cervical cancer reveals how treatment reshapes the tumor microenvironment and highlights targets for developing future immunotherapeutic approaches. See related commentary by Klopp, p. 1540.
{"title":"Chemoradiation Reprograms Tumor Cells and the Immune Microenvironment in Cervical Cancer.","authors":"Tito A Sandoval,Yize Li,Naoshad Muhammad,Tresha Desai,Reyka G Jayasinghe,Saman Zeeshan,Kay Jayachandran,Matthew J Inkman,Michael R Waters,Eliwaza Naomi S Msengi,Tyler R McKinnish,Ibrahim Hatipoglu,Ana Carolina Paschoalini Mafra,Muyassar Anwar,Donghua Hu,Dhaval P Bhatt,Varintra E Lander,R Jay Mashl,Andrew Houston,Liyun Chen,Jessika Contreras,Clifford G Robinson,Sherri R Davies,Julie Belmar,Shunqiang Li,Michael B Major,David G DeNardo,Stephanie Markovina,Brian T Edelson,Jin Zhang,Li Ding,Julie K Schwarz","doi":"10.1158/0008-5472.can-25-3776","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3776","url":null,"abstract":"Despite advances in screening and prevention, cervical cancer remains a leading cause of cancer-related deaths worldwide, underscoring the need for better treatments. In this study, we conducted a multicohort longitudinal study of human cervical tumors and the tumor microenvironment during chemoradiotherapy (CRT) and integrated RNA sequencing and single-cell transcriptomics to define the cellular and molecular programs shaping cell interactions and how CRT alters them. The analysis identified multiple therapeutic targets in CRT-resistant tumors, notably including MDM2, a key mediator of radiation responses in tumor and immune cells. MDM2 inhibition enhanced the effects of radiotherapy in human papillomavirus (HPV)-positive, TP53 wild-type cervical cancer cells; improved radiation response; and reshaped the immune landscape in preclinical models. These findings highlight the potential of combining MDM2 inhibition with CRT to overcome resistance and improve patient outcomes. The insights into therapy-induced changes in tumor and immune compartments could guide improved strategies against treatment-resistant HPV-positive cancers.SIGNIFICANCEMapping of the impact of chemoradiation on cellular interactions in cervical cancer reveals how treatment reshapes the tumor microenvironment and highlights targets for developing future immunotherapeutic approaches. See related commentary by Klopp, p. 1540.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 1","pages":"OF1-OF18"},"PeriodicalIF":11.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-20DOI: 10.1158/0008-5472.can-25-3255
Chu Han,Bingchao Zhao,Tianpeng Deng,Jingqi Huang,Fangfang Liu,Jiatai Lin,Shanshan Lyu,Longfei Wang,Cheng Lu,Changhong Liang,Hannah Y Wen,Zhenwei Shi,Xiaojing Guo,Zaiyi Liu
Despite the impressive performance across a range of applications, current computational pathology (CPath) models face significant diagnostic efficiency challenges due to their reliance on high-magnification whole-slide image analysis. This limitation compromises their clinical utility, especially in time-sensitive diagnostic scenarios and situations requiring efficient data transfer. To address these issues, we developed a computation- and communication-efficient framework called Magnification-AliGned Global-Local Transformer (MAG-GLTrans). The approach significantly reduced computational time, file transfer requirements, and storage overhead by enabling effective analysis using low-magnification inputs. The magnification alignment (MAG) mechanism employed self-supervised learning to bridge the information gap between low- and high-magnification levels by effectively aligning their feature representations. Through extensive evaluation across various fundamental CPath tasks, MAG-GLTrans demonstrated state-of-the-art classification performance while achieving remarkable efficiency gains, including up to 10.7× reduction in computational time and over 20× reduction in file transfer and storage requirements. Furthermore, the versatility of the MAG framework was demonstrated through two significant extensions: (1) its applicability as a feature extractor to enhance the efficiency of any CPath architecture and (2) its compatibility with existing foundation models, enabling them to process low-magnification inputs with minimal information loss. In a real-world clinical application, computer-assisted telepathology for intraoperative frozen section diagnosis of non-small cell lung carcinoma, MAG-GLTrans effectively recognized distinct tumor morphologies and accurately localized diagnostically relevant regions with low computational and communication costs. Together, these advancements position MAG-GLTrans as a particularly promising solution for time-sensitive applications, especially in the context of intraoperative frozen section diagnosis where both accuracy and efficiency are paramount.
{"title":"A Magnification Alignment Framework Enables Computation- and Communication-Efficient Computational Pathology.","authors":"Chu Han,Bingchao Zhao,Tianpeng Deng,Jingqi Huang,Fangfang Liu,Jiatai Lin,Shanshan Lyu,Longfei Wang,Cheng Lu,Changhong Liang,Hannah Y Wen,Zhenwei Shi,Xiaojing Guo,Zaiyi Liu","doi":"10.1158/0008-5472.can-25-3255","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3255","url":null,"abstract":"Despite the impressive performance across a range of applications, current computational pathology (CPath) models face significant diagnostic efficiency challenges due to their reliance on high-magnification whole-slide image analysis. This limitation compromises their clinical utility, especially in time-sensitive diagnostic scenarios and situations requiring efficient data transfer. To address these issues, we developed a computation- and communication-efficient framework called Magnification-AliGned Global-Local Transformer (MAG-GLTrans). The approach significantly reduced computational time, file transfer requirements, and storage overhead by enabling effective analysis using low-magnification inputs. The magnification alignment (MAG) mechanism employed self-supervised learning to bridge the information gap between low- and high-magnification levels by effectively aligning their feature representations. Through extensive evaluation across various fundamental CPath tasks, MAG-GLTrans demonstrated state-of-the-art classification performance while achieving remarkable efficiency gains, including up to 10.7× reduction in computational time and over 20× reduction in file transfer and storage requirements. Furthermore, the versatility of the MAG framework was demonstrated through two significant extensions: (1) its applicability as a feature extractor to enhance the efficiency of any CPath architecture and (2) its compatibility with existing foundation models, enabling them to process low-magnification inputs with minimal information loss. In a real-world clinical application, computer-assisted telepathology for intraoperative frozen section diagnosis of non-small cell lung carcinoma, MAG-GLTrans effectively recognized distinct tumor morphologies and accurately localized diagnostically relevant regions with low computational and communication costs. Together, these advancements position MAG-GLTrans as a particularly promising solution for time-sensitive applications, especially in the context of intraoperative frozen section diagnosis where both accuracy and efficiency are paramount.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"183 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.CAN-24-4977
Seongyeol Park, Kijong Yi, Jieun Lee, Myung Jin Yang, Joo-Hye Song, Joonoh Lim, Taewoo Kim, Seokhwi Kim, Su Yeon Kim, Hyung-Don Kim, Yoon Ho Kim, Sae Bom Lee, Yoo Jin Jung, Hansol Park, Jake June-Koo Lee, Yohan An, Jeonghwan Youk, Kwon Joong Na, Samina Park, Hyun Joo Lee, In Kyu Park, Chang Hyun Kang, Eui-Cheol Shin, Tae Min Kim, Won Do Heo, Charles Lee, Gou Young Koh, Sung-Yup Cho, Young Seok Ju, Young Tae Kim
Thymic epithelial tumors (TET), comprising various histologic types of thymomas and thymic carcinomas, originate from thymic epithelial cells (TEC). Each histologic type is typically associated with a distinct immune cell composition and clinical manifestation. A better understanding of the cellular origins and molecular pathways underlying this heterogeneity is needed to improve patient stratification and treatment. In this study, we conducted an integrated genomic and transcriptomic analysis of 124 thymomas and 13 thymic carcinomas, including 20 newly sequenced cases, combined with 117 cases from publicly available datasets. Single-cell transcriptomic data from murine thymic tissues across developmental stages were incorporated to further investigate potential cells of origin. This approach stratified TETs into three subgroups with different possible origins: GTF2I-mutant (GTF2I-type) thymomas, copy number-altered (CN-type) thymomas, and thymic carcinomas. GTF2I-type thymomas, carrying hotspot GTF2I mutations, displayed transcriptional profiles resembling thymic epithelial progenitors. In contrast, CN-type thymomas, characterized by frequent copy-number alterations and IRS4 oncogene transcriptional activation, showed expression patterns similar to differentiated TECs. Thymic carcinomas, with high mutational burdens, exhibited profiles comparable with thymic tuft cells. The three subgroups also differed markedly in transcriptional programs, including lipid metabolism and immune phenotypes. Early acquisition of chromosomal copy-number alterations in CN-type thymomas further supported different evolutionary paths among subgroups. Together, these findings provide insights into the cellular origins and tumorigenic processes of TETs and underscore the value of integrative genomics for accurate cancer classification.
Significance: Thymic epithelial tumors can be classified into three subgroups based on genomic features and potential cells of origin, highlighting the importance of integrative analyses for accurate classification and therapeutic discovery.
{"title":"Integrative Multiomic Classification Reveals Distinct Origins and Evolutionary Trajectories of Thymic Epithelial Tumors.","authors":"Seongyeol Park, Kijong Yi, Jieun Lee, Myung Jin Yang, Joo-Hye Song, Joonoh Lim, Taewoo Kim, Seokhwi Kim, Su Yeon Kim, Hyung-Don Kim, Yoon Ho Kim, Sae Bom Lee, Yoo Jin Jung, Hansol Park, Jake June-Koo Lee, Yohan An, Jeonghwan Youk, Kwon Joong Na, Samina Park, Hyun Joo Lee, In Kyu Park, Chang Hyun Kang, Eui-Cheol Shin, Tae Min Kim, Won Do Heo, Charles Lee, Gou Young Koh, Sung-Yup Cho, Young Seok Ju, Young Tae Kim","doi":"10.1158/0008-5472.CAN-24-4977","DOIUrl":"10.1158/0008-5472.CAN-24-4977","url":null,"abstract":"<p><p>Thymic epithelial tumors (TET), comprising various histologic types of thymomas and thymic carcinomas, originate from thymic epithelial cells (TEC). Each histologic type is typically associated with a distinct immune cell composition and clinical manifestation. A better understanding of the cellular origins and molecular pathways underlying this heterogeneity is needed to improve patient stratification and treatment. In this study, we conducted an integrated genomic and transcriptomic analysis of 124 thymomas and 13 thymic carcinomas, including 20 newly sequenced cases, combined with 117 cases from publicly available datasets. Single-cell transcriptomic data from murine thymic tissues across developmental stages were incorporated to further investigate potential cells of origin. This approach stratified TETs into three subgroups with different possible origins: GTF2I-mutant (GTF2I-type) thymomas, copy number-altered (CN-type) thymomas, and thymic carcinomas. GTF2I-type thymomas, carrying hotspot GTF2I mutations, displayed transcriptional profiles resembling thymic epithelial progenitors. In contrast, CN-type thymomas, characterized by frequent copy-number alterations and IRS4 oncogene transcriptional activation, showed expression patterns similar to differentiated TECs. Thymic carcinomas, with high mutational burdens, exhibited profiles comparable with thymic tuft cells. The three subgroups also differed markedly in transcriptional programs, including lipid metabolism and immune phenotypes. Early acquisition of chromosomal copy-number alterations in CN-type thymomas further supported different evolutionary paths among subgroups. Together, these findings provide insights into the cellular origins and tumorigenic processes of TETs and underscore the value of integrative genomics for accurate cancer classification.</p><p><strong>Significance: </strong>Thymic epithelial tumors can be classified into three subgroups based on genomic features and potential cells of origin, highlighting the importance of integrative analyses for accurate classification and therapeutic discovery.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1496-1513"},"PeriodicalIF":16.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.CAN-26-0226
Shulin Wang, Wafik S El-Deiry
{"title":"Editor's Note: Inducible Silencing of KILLER/DR5 In vivo Promotes Bioluminescent Colon Tumor Xenograft Growth and Confers Resistance to Chemotherapeutic Agent 5-Fluorouracil.","authors":"Shulin Wang, Wafik S El-Deiry","doi":"10.1158/0008-5472.CAN-26-0226","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-26-0226","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 6","pages":"1529"},"PeriodicalIF":16.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.can-25-4415
Jun Wu,Chen Chen,Xiaoxia Lv,Qiang Wang,Zhangding Wang,Yong Chen,Jiaqi Hou,Qingting Fan,Qinglin Ren,Chao Sun,Shichun Lu,Yusheng Shu,Shouyu Wang,Xiaolin Wang
Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with dismal clinical outcomes and limited treatment options. NAD(P)H quinone oxidoreductase 1 (NQO1) is classically characterized as a cytosolic oxidoreductase that prevents the formation of reactive oxygen species. Here, we demonstrated that NQO1 promoted ESCC progression and lung colonization via an enzymatic activity-independent mechanism. Integrated transcriptomic and direct RNA-binding analyses revealed that NQO1 acted as an RNA-binding protein to stabilize the mRNA encoding agrin (AGRN), thereby increasing AGRN expression. Upregulation of AGRN enhanced endothelial cytoskeletal organization by interacting with filamin A (FLNA) and stimulated angiogenesis through selective extracellular vesicle-mediated transfer. Structure-based screening identified the clinically approved agent panobinostat as a direct NQO1-binding compound that destabilized NQO1 and suppressed AGRN-dependent angiogenic signaling. Importantly, combined treatment with panobinostat and the anti-angiogenic agent anlotinib resulted in superior inhibition of tumor growth and vascularization compared with either monotherapy in patient-derived organoid xenograft models. Together, these findings uncover an enzymatic activity-independent RNA regulatory function of NQO1 in ESCC and provide a mechanistic rationale for targeting the NQO1/AGRN axis.
{"title":"A Non-canonical RNA-Binding Function of NQO1 Drives Angiogenesis in Esophageal Squamous Cell Carcinoma via Extracellular Vesicle-Mediated AGRN Transfer.","authors":"Jun Wu,Chen Chen,Xiaoxia Lv,Qiang Wang,Zhangding Wang,Yong Chen,Jiaqi Hou,Qingting Fan,Qinglin Ren,Chao Sun,Shichun Lu,Yusheng Shu,Shouyu Wang,Xiaolin Wang","doi":"10.1158/0008-5472.can-25-4415","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-4415","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with dismal clinical outcomes and limited treatment options. NAD(P)H quinone oxidoreductase 1 (NQO1) is classically characterized as a cytosolic oxidoreductase that prevents the formation of reactive oxygen species. Here, we demonstrated that NQO1 promoted ESCC progression and lung colonization via an enzymatic activity-independent mechanism. Integrated transcriptomic and direct RNA-binding analyses revealed that NQO1 acted as an RNA-binding protein to stabilize the mRNA encoding agrin (AGRN), thereby increasing AGRN expression. Upregulation of AGRN enhanced endothelial cytoskeletal organization by interacting with filamin A (FLNA) and stimulated angiogenesis through selective extracellular vesicle-mediated transfer. Structure-based screening identified the clinically approved agent panobinostat as a direct NQO1-binding compound that destabilized NQO1 and suppressed AGRN-dependent angiogenic signaling. Importantly, combined treatment with panobinostat and the anti-angiogenic agent anlotinib resulted in superior inhibition of tumor growth and vascularization compared with either monotherapy in patient-derived organoid xenograft models. Together, these findings uncover an enzymatic activity-independent RNA regulatory function of NQO1 in ESCC and provide a mechanistic rationale for targeting the NQO1/AGRN axis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.CAN-26-0229
Shengliang Zhang, Lanlan Zhou, Bo Hong, A Pieter J van den Heuvel, Varun V Prabhu, Noel A Warfel, Christina Leah B Kline, David T Dicker, Levy Kopelovich, Wafik S El-Deiry
{"title":"Editor's Note: Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.","authors":"Shengliang Zhang, Lanlan Zhou, Bo Hong, A Pieter J van den Heuvel, Varun V Prabhu, Noel A Warfel, Christina Leah B Kline, David T Dicker, Levy Kopelovich, Wafik S El-Deiry","doi":"10.1158/0008-5472.CAN-26-0229","DOIUrl":"10.1158/0008-5472.CAN-26-0229","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 6","pages":"1526"},"PeriodicalIF":16.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.CAN-26-0228
John P Plastaras, Seok-Hyun Kim, Yingqiu Y Liu, David T Dicker, Jay F Dorsey, James McDonough, George Cerniglia, Ramji R Rajendran, Anjali Gupta, Anil K Rustgi, J Alan Diehl, Charles D Smith, Keith T Flaherty, Wafik S El-Deiry
{"title":"Editor's Note: Cell Cycle-Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation.","authors":"John P Plastaras, Seok-Hyun Kim, Yingqiu Y Liu, David T Dicker, Jay F Dorsey, James McDonough, George Cerniglia, Ramji R Rajendran, Anjali Gupta, Anil K Rustgi, J Alan Diehl, Charles D Smith, Keith T Flaherty, Wafik S El-Deiry","doi":"10.1158/0008-5472.CAN-26-0228","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-26-0228","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 6","pages":"1527"},"PeriodicalIF":16.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1158/0008-5472.can-25-5539
Ethan J Vallebuona,Inna Smalley
The tumor microenvironment plays an important role in brain metastasis. To investigate microglial subtypes in the developing metastatic tumor microenvironment in this issue of Cancer Research, Tsuji and colleagues pioneer a cutting-edge approach for mapping the transcriptional fate of live, spatially identified cells using a method they call "opto-omics." Using a mouse model that enables microglia-specific transgenic expression of a photoconvertible fluorescent protein, the authors profile disease-associated microglia in spatial proximity to disseminated tumor cells (DTC) through intracerebral windows installed in the mouse skull. Microglia that spatially migrate to DTCs are photoconverted, and transcriptional profiling of these microglia reveals an overall enrichment in inflammatory gene programs with five distinct subpopulations corresponding to biological processes such as antigen presentation, type II IFN response, phagocytosis, TGFβ signaling, and tissue repair. This article describes a strategy to modulate the relative abundance of individual microglial subpopulations through pharmacologic perturbation of specific pathways, such as TGFβ, or through genetic ablation of "don't eat me" signals to reprogram protumor microglia. By developing opto-omics and demonstrating its functional integration with single-cell transcriptomics, the authors present a versatile platform for phenotypic profiling that may be applied in numerous areas of research. See related article by Tsuji et al., p. 1414.
{"title":"Spatially Resolved Opto-Omics Uncovers Functional Microglial Subtypes in Brain Metastasis.","authors":"Ethan J Vallebuona,Inna Smalley","doi":"10.1158/0008-5472.can-25-5539","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5539","url":null,"abstract":"The tumor microenvironment plays an important role in brain metastasis. To investigate microglial subtypes in the developing metastatic tumor microenvironment in this issue of Cancer Research, Tsuji and colleagues pioneer a cutting-edge approach for mapping the transcriptional fate of live, spatially identified cells using a method they call \"opto-omics.\" Using a mouse model that enables microglia-specific transgenic expression of a photoconvertible fluorescent protein, the authors profile disease-associated microglia in spatial proximity to disseminated tumor cells (DTC) through intracerebral windows installed in the mouse skull. Microglia that spatially migrate to DTCs are photoconverted, and transcriptional profiling of these microglia reveals an overall enrichment in inflammatory gene programs with five distinct subpopulations corresponding to biological processes such as antigen presentation, type II IFN response, phagocytosis, TGFβ signaling, and tissue repair. This article describes a strategy to modulate the relative abundance of individual microglial subpopulations through pharmacologic perturbation of specific pathways, such as TGFβ, or through genetic ablation of \"don't eat me\" signals to reprogram protumor microglia. By developing opto-omics and demonstrating its functional integration with single-cell transcriptomics, the authors present a versatile platform for phenotypic profiling that may be applied in numerous areas of research. See related article by Tsuji et al., p. 1414.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"266 1","pages":"1345-1346"},"PeriodicalIF":11.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：