Molecular Cancer Research最新文献_第7页

Modeling of Capicua Family Fusion Oncoprotein-Driven Cancers Reveals Gene-Specific Functionality. Capicua家族融合癌蛋白驱动癌症的建模揭示了基因特异性功能。

IF 5.8 2区医学

Molecular Cancer Research Pub Date : 2026-05-04 DOI: 10.1158/1541-7786.MCR-25-0624

Cuyler Luck, Yongfeng Luo, Elena Vasileva, Kyle A Jacobs, Julia Riad, Christopher D Macaraig, Rovingaile Kriska M Ponce, James F Amatruda, Ross A Okimoto

{"title":"Modeling of Capicua Family Fusion Oncoprotein-Driven Cancers Reveals Gene-Specific Functionality.","authors":"Cuyler Luck, Yongfeng Luo, Elena Vasileva, Kyle A Jacobs, Julia Riad, Christopher D Macaraig, Rovingaile Kriska M Ponce, James F Amatruda, Ross A Okimoto","doi":"10.1158/1541-7786.MCR-25-0624","DOIUrl":"10.1158/1541-7786.MCR-25-0624","url":null,"abstract":"Clinical divergence between patients harboring Capicua (CIC) rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft-tissue tumors whereas CIC::NUTM1 fusions typically localize to the central nervous system (brain/spinal cord). The basis for these differences is poorly understood because of a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies and in genetic zebrafish models. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 because of a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity.Implications: These first-generation synthetic tools illuminate partner gene-specific mechanistic biology while providing an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"337-355"},"PeriodicalIF":5.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12930430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030430","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}

引用次数: 0

Tumor Cell-Derived Microparticles Induced by Methotrexate Reprogram Neutrophil Antitumor Response via Lysosomal ROS-Mediated Degranulation. 甲氨蝶呤重编程中性粒细胞通过溶酶体ROS介导的脱颗粒诱导肿瘤细胞源性微粒的抗肿瘤反应。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0615

Xiaojie Zhang, Kai Chen, Meng Zhu, Siyu Gao, Junyi Wang, Xingyu Si, Ru Jia, Chenhao Jin, Junhong Ding, Xingyi Hu, Haobing Li, Yunfeng Huang, Meilin Yi, Ebrahim Abdo, Keqing Shi, Ke Tang, Pingwei Xu

{"title":"Tumor Cell-Derived Microparticles Induced by Methotrexate Reprogram Neutrophil Antitumor Response via Lysosomal ROS-Mediated Degranulation.","authors":"Xiaojie Zhang, Kai Chen, Meng Zhu, Siyu Gao, Junyi Wang, Xingyu Si, Ru Jia, Chenhao Jin, Junhong Ding, Xingyi Hu, Haobing Li, Yunfeng Huang, Meilin Yi, Ebrahim Abdo, Keqing Shi, Ke Tang, Pingwei Xu","doi":"10.1158/1541-7786.MCR-25-0615","DOIUrl":"10.1158/1541-7786.MCR-25-0615","url":null,"abstract":"Neutrophils are one of the most important immune cells in the tumor microenvironment, and they affect the immunosuppression status by directly supporting the tumor progression or indirectly impairing T-cell antitumor response. Although recent evidence indicates that neutrophils determine the success of tumor immunotherapy, how to activate the innate immune system antitumor response still lags out. In this study, we provide evidence that the methotrexate-packaged tumor cell-derived microparticles (MTX-MP) activate neutrophil antitumor response by directly releasing tumor cytotoxic microparticles, increasing tumor-infiltrated CD8+ T cells, and promoting CD8+ T-cell antitumor response. Strikingly, mitochondrial-lysosomal membrane contacts mediate NADH translocation to lysosomal compartments. Within lysosomes, ENOX2 catalyzes NADH oxidation to generate lysosomal reactive oxygen species, which induce Ca2+ efflux via lysosomal channels. This calcium surge triggers neutrophil degranulation, thereby promoting cytotoxic microparticle release. By performing the combination of MTX-MP-activated neutrophils and OT-1 CD8+ T-cell transfer, we found that the long-term survival rate improved in OVA-expressing Lewis lung carcinoma models.Implications: Our findings revealed a new way by which activated-neutrophils release microparticles to kill tumor cells and provided a potential combinatorial therapeutic strategy for tumor immunotherapy.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"293-308"},"PeriodicalIF":4.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MTHFD2-Mediated Ubiquitination and Degradation of FOXO1 Promote Tongue Squamous Cell Carcinoma Progression. mthfd2介导的泛素化和fox01降解促进舌鳞状细胞癌的进展。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0724

Aikebaier Tuohuti, Lucheng Fang, Zehua Lin, Sa Wu, Weisong Cai, Xiaoping Ming, Zhe Chen, Qiang Xie, Qiuyang Fu, Xiaoqi Sun, Xiong Chen

{"title":"MTHFD2-Mediated Ubiquitination and Degradation of FOXO1 Promote Tongue Squamous Cell Carcinoma Progression.","authors":"Aikebaier Tuohuti, Lucheng Fang, Zehua Lin, Sa Wu, Weisong Cai, Xiaoping Ming, Zhe Chen, Qiang Xie, Qiuyang Fu, Xiaoqi Sun, Xiong Chen","doi":"10.1158/1541-7786.MCR-25-0724","DOIUrl":"10.1158/1541-7786.MCR-25-0724","url":null,"abstract":"Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a pivotal enzyme in one-carbon metabolism, is significantly overexpressed in tongue squamous cell carcinoma (TSCC) and correlates with poor patient prognosis. Functional studies demonstrate that MTHFD2 drives TSCC proliferation and migration in vitro and in vivo, whereas its inhibition suppresses tumor progression. Mechanistically, MTHFD2 orchestrates a dual posttranslational modification cascade: Through its enzymatic activity, it simultaneously induces forkhead box O1 (FOXO1) hypermethylation and ubiquitination, ultimately triggering ubiquitin-proteasome degradation of this tumor suppressor. This methylation-primed degradation axis is clinically validated by the inverse MTHFD2-high/FOXO1-low expression pattern in TSCC specimens, which predicts adverse outcomes. Critically, pharmacologic inhibition of MTHFD2 (e.g., DS18561882) blocks FOXO1 degradation, establishing the MTHFD2-FOXO1 axis as a promising therapeutic target for TSCC through its novel metabolic-epigenetic regulatory mechanism.Implications: This study identifies the MTHFD2-FOXO1 axis as a druggable metabolic-epigenetic pathway in TSCC, providing both a prognostic marker and a therapeutic target.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"270-282"},"PeriodicalIF":4.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target. 蛋白酶活化受体-2促进转移：一个新的治疗靶点。

IF 5.8 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0788

Amando A Strong, Marguerite S Buzza, Toni M Antalis

{"title":"Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.","authors":"Amando A Strong, Marguerite S Buzza, Toni M Antalis","doi":"10.1158/1541-7786.MCR-25-0788","DOIUrl":"10.1158/1541-7786.MCR-25-0788","url":null,"abstract":"Tumor metastasis remains the most lethal and elusive aspect of cancer progression, accounting for the vast majority of cancer-related deaths despite significant advances in treatment. Although our understanding of the molecular mechanisms underlying metastasis has improved over the past decades, effective therapeutic interventions remain limited. Protease-activated receptor-2 (PAR-2) is one of only four G protein-coupled receptors (GPCR) that are uniquely activated by a proteolytic cleavage event that generates a tethered ligand derived from the receptor itself, in contrast to other GPCRs which are activated by soluble ligands present in the extracellular environment. PAR-2, and many of the proinflammatory serine proteases that activate it, is overexpressed in advanced-stage cancers. Emerging evidence implicates PAR-2 signaling in multiple cellular processes that drive metastatic progression. Pharmacologic inhibitors of PAR-2, initially developed to treat chronic pain and inflammatory conditions, may be repurposed to exploit metastatic vulnerabilities in tumors while sparing normal physiologic functions. This review examines the molecular mechanisms by which PAR-2 signaling promotes metastasis and explores the potential of PAR-2-targeted antagonists-alone or in combination with existing cancer therapies-to improve clinical outcomes in patients with advanced malignancies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"207-220"},"PeriodicalIF":5.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13040814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165994","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}

引用次数: 0

Genomic Profile and Clinicopathologic Analyses of Wild-Type Gastrointestinal Stromal Tumors. 野生型胃肠道间质瘤的基因组图谱和临床病理分析。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0524

Lin Sun, Jiaxin Li, Huimin Liu, Jing Chen, Shihui Wang, Rui Deng, Yan Sun

{"title":"Genomic Profile and Clinicopathologic Analyses of Wild-Type Gastrointestinal Stromal Tumors.","authors":"Lin Sun, Jiaxin Li, Huimin Liu, Jing Chen, Shihui Wang, Rui Deng, Yan Sun","doi":"10.1158/1541-7786.MCR-25-0524","DOIUrl":"10.1158/1541-7786.MCR-25-0524","url":null,"abstract":"The driver genes of wild-type gastrointestinal stromal tumors (WT-GIST), particularly quadruple WT-GISTs (qWT-GIST), remain unclear. In this study, we collected 119 WT-GISTs from two cohorts and analyzed their clinicopathologic and genomic features, particularly for qWT-GISTs. Next-generation sequencing (NGS) revealed several fusion genes and gene mutations, such as ARID1B, SETD2, and PLCG2, in qWT-GISTs. Further integrated Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed significantly enriched signaling pathways in qWT-GISTs, including the hypoxia-inducible factor-1 (HIF-1). For qWT-GISTs, large tumors or a high mitotic index prompted a shorter recurrence-free survival (RFS) and a high mitotic index or involvement of the HIF-1 pathway prompted a shorter overall survival (OS); however, neither RFS nor OS was prolonged by postoperative adjuvant therapy. In addition, compared with succinate dehydrogenase complex (SDH)-deficient GISTs, qWT-GISTs were less frequently found in the stomach and less frequently presented as high mitotic index; compared with RAS-related GISTs, qWT-GISTs were more frequently found in the stomach. Stratified analyses showed, in patients with low recurrence risk, qWT-GISTs had better RFS than SDH-deficient GISTs. In patients with high recurrence risk or with postoperative adjuvant therapy, qWT-GISTs presented worse OS than SDH-deficient GISTs. In summary, qWT-GISTs exhibited unique clinicopathologic characteristics and outcomes compared with SDH-deficient and RAS-related GISTs, suggesting that they should be managed using different treatment and follow-up strategies, especially stratified management. Considering the rarity and heterogeneity of WT-GISTs, a regulatory detection procedure should be established for WT-GISTs, including NGS for qWT-GISTs, to identify the molecular mechanisms and potential therapeutic targets.Implications: WT-GISTs are heterogenous tumors which should be managed using different treatments and follow-up strategies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"232-241"},"PeriodicalIF":4.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

circNEIL3 Stabilizes SPI1 mRNA and Promotes Glioma Progression and Temozolomide Resistance by Binding to U2AF2. circNEIL3稳定SPI1 mRNA并通过与U2AF2结合促进胶质瘤进展和替莫唑胺耐药性。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0321

Zhi Xue, Qian Peng, Zhonghao Liu, Shengli Sun

{"title":"circNEIL3 Stabilizes SPI1 mRNA and Promotes Glioma Progression and Temozolomide Resistance by Binding to U2AF2.","authors":"Zhi Xue, Qian Peng, Zhonghao Liu, Shengli Sun","doi":"10.1158/1541-7786.MCR-25-0321","DOIUrl":"10.1158/1541-7786.MCR-25-0321","url":null,"abstract":"Temozolomide (TMZ) resistance is an urgent problem in the treatment of glioma. circNEIL3 is related to the malignant progression of glioma. Nevertheless, the function of circNEIL3 in TMZ resistance is still unclear. In this study, we found that circNEIL3 is overexpressed in glioma tissues and cells and is related to TMZ resistance. Cell experiments and mouse experiments have shown that inhibiting the expression of circNEIL3 can enhance the sensitivity of glioma cells to TMZ. RNA immunoprecipitation and other molecular experiments demonstrated that circNEIL3 and the RNA-binding protein U2 small nuclear RNA auxiliary factor 2 (U2AF2) interact with each other and partially colocalize in cells. SPI1 was highly expressed in glioma, more significantly in TMZ-resistant tissues, and correlated with circNEIL3 expression. Furthermore, we discovered that U2AF2 interacts with SPI1 mRNA as well, and circNEIL3 and U2AF2 together regulate the expression and mRNA stability of SPI1. More importantly, SPI1 silencing inhibited the malignant progression of cells and partially reversed the effects of circNEIL3 on glioma cell proliferation and apoptosis. In conclusion, circNEIL3 stabilizes SPI1 mRNA expression by binding to U2AF2, thereby promoting glioma progression and TMZ resistance.Implications: Our findings offer new mechanistic insights into glioma drug resistance, and targeting the circNEIL3/U2AF2/SPI1 axis represents a promising approach to counteract TMZ resistance in gliomas.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"283-292"},"PeriodicalIF":4.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetically Engineered Human iPS Cell-Derived Kidney Organoid Recapitulates an Early Stage of ALK Fusion Gene-Associated Renal Tumorigenesis. 基因工程人类iPS细胞衍生的肾类器官再现了ALK融合基因相关肾肿瘤发生的早期阶段。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0043

Go Noguchi, Masaya Baba, Shinji Ohtake, Ryosuke Jikuya, Taku Mitome, Sachi Kawaura, Kota Aomori, Yasuhiro Iribe, Hirotaka Nagasaka, Luh Ade Wilan Krisna, Shintaro Funasaki, Erika Muraoka, Satoshi Fujii, Toyonori Tsuzuki, Ikuma Kato, Mitsuko Furuya, Yoji Nagashima, Hidekazu Nishizawa, Tomomi Kamba, Shohei Kuraoka, Tatsukata Kawagoe, Nobuhisa Mizuki, Tomoyuki Tatenuma, Daiki Ueno, Takashi Kawahara, Hiroki Ito, Mitsuru Komeya, Yusuke Ito, Kentaro Muraoka, Hiroji Uemura, Tomohiko Tamura, Takehiko Ogawa, Toshio Suda, Masahiro Yao, Kazuhide Makiyama, Hidewaki Nakagawa, Brian M Shuch, Christopher J Ricketts, Laura S Schmidt, W Marston Linehan, Ryuichi Nishinakamura, Hisashi Hasumi

{"title":"Genetically Engineered Human iPS Cell-Derived Kidney Organoid Recapitulates an Early Stage of ALK Fusion Gene-Associated Renal Tumorigenesis.","authors":"Go Noguchi, Masaya Baba, Shinji Ohtake, Ryosuke Jikuya, Taku Mitome, Sachi Kawaura, Kota Aomori, Yasuhiro Iribe, Hirotaka Nagasaka, Luh Ade Wilan Krisna, Shintaro Funasaki, Erika Muraoka, Satoshi Fujii, Toyonori Tsuzuki, Ikuma Kato, Mitsuko Furuya, Yoji Nagashima, Hidekazu Nishizawa, Tomomi Kamba, Shohei Kuraoka, Tatsukata Kawagoe, Nobuhisa Mizuki, Tomoyuki Tatenuma, Daiki Ueno, Takashi Kawahara, Hiroki Ito, Mitsuru Komeya, Yusuke Ito, Kentaro Muraoka, Hiroji Uemura, Tomohiko Tamura, Takehiko Ogawa, Toshio Suda, Masahiro Yao, Kazuhide Makiyama, Hidewaki Nakagawa, Brian M Shuch, Christopher J Ricketts, Laura S Schmidt, W Marston Linehan, Ryuichi Nishinakamura, Hisashi Hasumi","doi":"10.1158/1541-7786.MCR-25-0043","DOIUrl":"10.1158/1541-7786.MCR-25-0043","url":null,"abstract":"Although kidney cancer arises from a variety of nephron cells with diverse characteristics and develops intratumor heterogeneity, a model to elucidate these complexities is incompletely developed. In this study, we report a genetically engineered human induced pluripotent stem cell-derived kidney organoid (HKO) model, which may recapitulate an early stage of renal tumorigenesis. When we overexpressed the VCL-ALK fusion gene, a renal oncogene, in HKO, tubular cells proliferated, and this proliferation was sustained under long-term culture or hypoxic conditions. In addition, the proliferating tubular cells migrated into the renal parenchyma of host mice upon transplantation. The deconvolution analysis and IHC revealed that the proliferating tubular cells could be arrested at an immature tubular progenitor stage with increased expressions of LIM homeobox protein 1 and jagged canonical Notch ligand 1, critical regulators of nephrogenesis. Our HKO model advances our understanding of renal tumorigenesis in the context of the trajectory of nephron development.Implications: Dysregulated nephron developmental machinery leads to aberrant cell proliferation of immature renal tubules.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"221-231"},"PeriodicalIF":4.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Landscape of Allele-Specific Expression in Prostate Cancer Reveals Recurrent, Stage-Specific Events in AR Signaling and Resistance Pathways. 前列腺癌中等位基因特异性表达的图谱揭示了AR信号传导和耐药途径中复发性、分期特异性事件。

IF 5.8 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0754

Margaret Tsui, Kevin Hu, Hanbing Song, Sarah C Hsu, Yih-An Chen, Lorraine Nuniz, Julia H Pham, Chih-Hao Chang, Keliana S F Hui, David A Quigley, Jingjing Li, Franklin W Huang

{"title":"Landscape of Allele-Specific Expression in Prostate Cancer Reveals Recurrent, Stage-Specific Events in AR Signaling and Resistance Pathways.","authors":"Margaret Tsui, Kevin Hu, Hanbing Song, Sarah C Hsu, Yih-An Chen, Lorraine Nuniz, Julia H Pham, Chih-Hao Chang, Keliana S F Hui, David A Quigley, Jingjing Li, Franklin W Huang","doi":"10.1158/1541-7786.MCR-25-0754","DOIUrl":"10.1158/1541-7786.MCR-25-0754","url":null,"abstract":"The effects of cis-regulatory alterations in prostate cancer are insufficiently characterized, presenting an opportunity to discover driver genes and therapeutic targets. To comprehensively study these effects, we identify genes undergoing allele-specific expression (ASE) in localized prostate cancer and metastatic castration-resistant prostate cancer (mCRPC) samples. By defining recurrent ASE events across prostate tissue and tumor-enriched ASE, we develop CASEDI, a computational framework for prioritizing cancer drivers by integrating ASE and clinical data. CASEDI reveals genes showing recurrent ASE and altered expression in prostate cancer, including AR-regulated and oncogenic ACSM1. mCRPC samples show enrichment of ASE in DNA repair, resistance pathways, and oncogenes and increased frequency of monoallelic expression (MAE) compared with localized tumors. We define an mCRPC gene signature based on MAE status that identifies a subgroup of localized patients with worse prognosis. Using ASE analysis, we expand the landscape of cis-regulatory events in prostate cancer to inform the identification of additional therapeutic targets.Implications: This study develops a framework for identifying cancer drivers using prostate cancer ASE data, generates a comprehensive dataset of ASE in prostate cancer and highlights candidate targets in tumorigenesis and metastasis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"242-257"},"PeriodicalIF":5.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990109","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}

引用次数: 0

MIG-6 Regulates HDAC1-Mediated Angiogenesis and Tumorigenesis in PTEN-Deficient Endometrioid Endometrial Cancer. MIG-6调控hdac1介导的pten缺陷子宫内膜样癌血管生成和肿瘤发生。

IF 5.8 2区医学

Molecular Cancer Research Pub Date : 2026-04-02 DOI: 10.1158/1541-7786.MCR-25-0544

Shamsun Nahar, Jiyoung Yu, Haeam Lee, Dinh Nam Tran, Rong Li, Tae Hoon Kim, Jin-Seok Jung, Kyunggon Kim, Jung-Yoon Yoo, Jae-Wook Jeong

{"title":"MIG-6 Regulates HDAC1-Mediated Angiogenesis and Tumorigenesis in PTEN-Deficient Endometrioid Endometrial Cancer.","authors":"Shamsun Nahar, Jiyoung Yu, Haeam Lee, Dinh Nam Tran, Rong Li, Tae Hoon Kim, Jin-Seok Jung, Kyunggon Kim, Jung-Yoon Yoo, Jae-Wook Jeong","doi":"10.1158/1541-7786.MCR-25-0544","DOIUrl":"10.1158/1541-7786.MCR-25-0544","url":null,"abstract":"Endometrioid endometrial cancer (EEC) is the most prevalent gynecologic malignancy, yet no targeted therapies are currently approved by the FDA specifically for it. To identify therapeutic targets for EEC, we performed transcriptomic and proteomic analyses in genetically engineered preclinical cancer models, including uterine-specific phosphatase and tensin homolog (Pten)-deficient (Ptend/d) mice and Ptend/d mice with additional overexpression of the tumor suppressor mitogen-inducible gene 6 (Mig-6) that develop EEC. Transcriptomic analysis revealed significant inhibition of immune, inflammatory, and angiogenesis pathways, with hypoxia-inducible factor-1α (HIF1α) as a key upstream regulator. Interactome and immunoprecipitation analyses identified HDAC1 as a MIG-6-interacting protein that mediates angiogenic signaling in PTEN-deficient endometrial cancer. MIG-6 overexpression suppressed HDAC1 activity and downstream HIF1α-driven angiogenesis. Pharmacologic inhibition of HDAC1 with panobinostat recapitulated the tumor-suppressive effects observed with MIG-6 overexpression. These findings suggest that HDAC1 may represent a potential therapeutic target in EEC and that HDAC inhibition can attenuate early tumor progression and angiogenic signaling in preclinical models.Implications: This study identifies the MIG-6-HDAC1 axis as a key regulator of angiogenesis in EEC, highlighting HDAC1 inhibition as a promising targeted therapeutic strategy for early tumor suppression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"258-269"},"PeriodicalIF":5.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12935093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011374","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}

引用次数: 0

Correction: GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress. 更正：GAS6/AXL抑制通过增加DNA损伤和增强复制应激增强卵巢癌对化疗和PARP抑制的敏感性。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-03-03 DOI: 10.1158/1541-7786.MCR-26-0075

Mary M Mullen, Elena Lomonosova, Michael D Toboni, Alyssa Oplt, Emily Cybulla, Barbara Blachut, Peinan Zhao, Hollie Noia, Daniel Wilke, Erinn B Rankin, Lindsay M Kuroki, Andrea R Hagemann, Ian S Hagemann, Carolyn K McCourt, Premal H Thaker, David G Mutch, Matthew A Powell, Nima Mosammaparast, Alessandro Vindigni, Katherine C Fuh

引用次数: 0