Molecular Cancer Research最新文献_第2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 4.7 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":4.7,"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

HLA Class I Expression is Associated with Increased Immune Cell Density and PTEN Loss in Prostate Cancer. HLA I类表达与前列腺癌中免疫细胞密度增加和PTEN丢失相关

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-05-01 DOI: 10.1158/1541-7786.MCR-25-1264

Adrianna Amaral, Thiago Vidotto, Juhyung Woo, Michael Rubenstein, Jiayun Lu, Carolina Gomes-Alexandre, Angelo M De Marzo, Karen Sfanos, Janielle Maynard, Ezra Baraban, Laura A Sena, Mark C Markowski, Emmanuel S Antonarakis, Corinne Joshu, Kaushal Asrani, Tamara L Lotan

{"title":"HLA Class I Expression is Associated with Increased Immune Cell Density and PTEN Loss in Prostate Cancer.","authors":"Adrianna Amaral, Thiago Vidotto, Juhyung Woo, Michael Rubenstein, Jiayun Lu, Carolina Gomes-Alexandre, Angelo M De Marzo, Karen Sfanos, Janielle Maynard, Ezra Baraban, Laura A Sena, Mark C Markowski, Emmanuel S Antonarakis, Corinne Joshu, Kaushal Asrani, Tamara L Lotan","doi":"10.1158/1541-7786.MCR-25-1264","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-1264","url":null,"abstract":"Human leukocyte antigen Class I (HLA-I) downregulation in prostate cancer may contribute to tumor immune evasion. We digitally quantified HLA-I protein expression in a cohort of racially diverse and molecularly characterized prostatectomy specimens, as well as additional cohorts of metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC). We confirm that HLA-I protein expression is negatively associated with intragenic methylation of major HLA-I genes, downregulated in tumor compared to benign glands, but not associated with race, genetic ancestry or clinicopathologic parameters in primary prostate cancer. Compared to matched primary tumor tissue, HLA-I expression is higher in HSPC pelvic lymph node metastases and increased primary tumor expression is inversely associated with metastasis among self-identified White, but not Black, patients. HLA-I expression in primary tumors is positively correlated with infiltrating immune cell densities, consistent with its established role in tumor cell immunogenicity. Surprisingly, primary tumors with PTEN loss show significantly higher HLA-I expression than those with intact PTEN, and this finding is validated in pre-clinical cell line and animal models, with a similar (nonsignificant) trend in mCRPC. Implications: The novel finding that PTEN loss is associated with higher tumoral HLA-I expression is concordant with observed increased immune cell infiltrates in tumors lacking PTEN, and may be relevant for precision medicine therapeutic approaches.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818022","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

YTHDC1 promotes triple-negative breast cancer cell proliferation and stemness by regulating BACH1 mRNA stability in an m6A-dependent manner. YTHDC1以m6a依赖的方式调节BACH1 mRNA的稳定性，促进三阴性乳腺癌细胞的增殖和干细胞性。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-24 DOI: 10.1158/1541-7786.MCR-25-0602

Shulin Huang, Haihui Gong, Jing Xie, Ou Yue

{"title":"YTHDC1 promotes triple-negative breast cancer cell proliferation and stemness by regulating BACH1 mRNA stability in an m6A-dependent manner.","authors":"Shulin Huang, Haihui Gong, Jing Xie, Ou Yue","doi":"10.1158/1541-7786.MCR-25-0602","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0602","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by a high mortality rate and limited treatment options. The mechanism by which YTHDC1 contributes to TNBC progression remains to be investigated. To investigate the role of YTHDC1 in TNBC, we performed in vitro real-time quantitative polymerase chain reaction (qRT-PCR), western blot (WB), cell counting kit-8 (CCK-8), colony formation, and sphere formation assays to evaluate its impacts on TNBC cell proliferation and stemness. Fluorescence in situ hybridization (FISH) and RNA immunoprecipitation (RIP) were employed to identify the binding sites of YTHDC1 on BACH1 mRNA. The stability of BACH1 mRNA following actinomycin D (ActD) treatment was analyzed after YTHDC1 silencing. Additionally, functional assays assessed the ability of BACH1 overexpression to counteract the inhibitory effects of YTHDC1 silencing on TNBC cell proliferation and stemness. We found that YTHDC1 expression was significantly elevated in TNBC tissues and cells. Silencing YTHDC1 inhibited cell proliferation, colony formation and sphere formation, and reduced the expression of stemness markers (Nanog, Oct4, and SOX2). YTHDC1 silencing also inhibited BACH1 mRNA nuclear export, leading to an increased nucleoplasmic ratio of BACH1 mRNA. Mechanistic studies revealed that YTHDC1 and m6A modifications significantly enriched on BACH1 mRNA, while YTHDC1 silencing reduced its stability. Importantly, BACH1 overexpression rescued the inhibitory effects of YTHDC1 silencing on TNBC cell proliferation and stemness marker expression. Collectively, YTHDC1 regulates BACH1 expression in an m6A-dependent mechanism, contributing to TNBC progression. Implications: Our findings provide a rationale for further investigation of the YTHDC1/BACH1 axis as a potential therapeutic target in TNBC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777126","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

Comparative ASCL1 interactome analysis reveals CDK2-Cyclin A2 as suppressors of differentiation in MYCN-amplified neuroblastoma. 比较ASCL1相互作用组分析显示CDK2-Cyclin A2是mycn扩增的神经母细胞瘤分化的抑制因子。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-14 DOI: 10.1158/1541-7786.MCR-24-0943

Lidiya Mykhaylechko, Roshna L Gomez, Laura M Woods, Evangelia K Papachristou, Revathy Ramachandran, Jethro Lundie-Brown, Rosalind Drummond, Daniel Marcos, Fiona M Y Abou Grealy, Shakhzada Ibragimova, Fahad R Ali, Jason Carroll, Anna Philpott

{"title":"Comparative ASCL1 interactome analysis reveals CDK2-Cyclin A2 as suppressors of differentiation in MYCN-amplified neuroblastoma.","authors":"Lidiya Mykhaylechko, Roshna L Gomez, Laura M Woods, Evangelia K Papachristou, Revathy Ramachandran, Jethro Lundie-Brown, Rosalind Drummond, Daniel Marcos, Fiona M Y Abou Grealy, Shakhzada Ibragimova, Fahad R Ali, Jason Carroll, Anna Philpott","doi":"10.1158/1541-7786.MCR-24-0943","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0943","url":null,"abstract":"Neuroblastoma is a heterogeneous paediatric cancer arising from developmentally arrested neuronal precursors, where restoring differentiation offers therapeutic promise. ASCL1, a pro-neural transcription factor, is widely expressed in neuroblastoma and can drive either proliferation or differentiation depending on the cellular context. Here, we show that distinct MYCN-amplified neuroblastoma cell lines exhibit differing differentiation responses to ASCL1 overexpression. By comparing genome-wide ASCL1 chromatin binding, transcriptional changes, and protein-protein interactions, we found that ASCL1 binds more extensively to neuronal proteins in a cell line that is more susceptible to ASCL1-driven differentiation, but associates with cell cycle regulators in less responsive cells. We show that CDK2-Cyclin A2 bind ASCL1 in less responsive cells, with CDK-mediated phosphorylation of ASCL1 limiting the ability of ASCL1 to drive differentiation. Implications: Our study reveals that context-dependent interactions of ASCL1 with protein partners on the chromatin control its ability to re-engage a differentiation program in neuroblastoma.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675425","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

The SNHG15/miR-451a/Caveolin-1 Axis Promotes Oxaliplatin Resistance in Gastric Cancer Cells by Regulating Fatty Acid β-oxidation. SNHG15/miR-451a/Caveolin-1轴通过调节脂肪酸β-氧化促进胃癌细胞对奥沙利铂的耐药。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-13 DOI: 10.1158/1541-7786.MCR-25-0154

Yi Wang, Zhongshi Hong, Jintian Song, Jianping Jiang, Zhihui Jiang, Shu Chen, Luchuan Chen, Hui Yu, Chengzhi Qiu, Shenghong Wei

{"title":"The SNHG15/miR-451a/Caveolin-1 Axis Promotes Oxaliplatin Resistance in Gastric Cancer Cells by Regulating Fatty Acid β-oxidation.","authors":"Yi Wang, Zhongshi Hong, Jintian Song, Jianping Jiang, Zhihui Jiang, Shu Chen, Luchuan Chen, Hui Yu, Chengzhi Qiu, Shenghong Wei","doi":"10.1158/1541-7786.MCR-25-0154","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0154","url":null,"abstract":"Gastric cancer is a common malignant tumor of the digestive tract. Chemotherapy resistance severely limits the therapeutic effect of this disease. The ceRNA regulatory network is widely involved in the occurrence and development of various cancers and is also closely related to the generation of drug resistance. However, the underlying molecular mechanism remains to be further elucidated. This study investigated the molecular mechanism by which the lncRNA SNHG15/miR-451a/ Caveolin-1(CAV1) axis mediates oxaliplatin resistance in gastric cancer through regulating fatty acid β-oxidation. Through analysis using the TCGA database and qRT-PCR, it was found that SNHG15 was highly expressed in gastric cancer tissues, while miR-451a was lowly expressed. Bioinformatics prediction combined with dual luciferase and RIP experiments confirmed that SNHG15 could act as a molecular sponge for miR-451a, and CAV1 was the downstream target gene of miR-451a. Functional experiments demonstrated that knockdown of miR-451a or overexpression of CAV1 could promote cell proliferation, inhibit apoptosis, and alleviate G0/G1 phase arrest, while enhancing fatty acid β-oxidation. In vivo experiments further confirmed that the SNHG15/miR-451a/CAV1 axis affected gastric cancer oxaliplatin resistance by regulating fatty acid β-oxidation. Implications: This study revealed that SNHG15 inhibits miR-451a to upregulate CAV1 expression, thereby regulating fatty acid β-oxidation and influencing gastric cancer oxaliplatin resistance, providing new biomarkers and potential therapeutic targets for gastric cancer oxaliplatin resistance.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675401","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

StarD5 Regulates Cholesterol Homeostasis to Promote Colorectal Cancer Progression and the Cancer Stem Cell Phenotype. StarD5调节胆固醇稳态促进结直肠癌进展和癌症干细胞表型

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-09 DOI: 10.1158/1541-7786.MCR-23-1084

Chetna Sharon, Daniel Rodriguez-Agudo, Rio S Boothello, Shoja M Haneefa, William M Pandak, Gregorio Gil, Bhaumik B Patel

{"title":"StarD5 Regulates Cholesterol Homeostasis to Promote Colorectal Cancer Progression and the Cancer Stem Cell Phenotype.","authors":"Chetna Sharon, Daniel Rodriguez-Agudo, Rio S Boothello, Shoja M Haneefa, William M Pandak, Gregorio Gil, Bhaumik B Patel","doi":"10.1158/1541-7786.MCR-23-1084","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-1084","url":null,"abstract":"An aberration in cellular, especially plasma membrane (PM), cholesterol level is arguably the most critical targetable hallmark of colorectal cancer (CRC) and CRC stem cell (CRCSC) phenotypes. We recently identified StarD5 as an intracellular cholesterol transport protein that regulates PM cholesterol levels. Here, we show that StarD5 protein levels are significantly elevated in most human CRC tissues compared to adjacent normal mucosa, with a preferential increase in the epithelial compartment. Additionally, allograft growth in StarD5 knockout mice was largely unaffected. StarD5 levels were particularly elevated in CRCSCs compared to non-CRCSCs in several colon cancer cell lines and primary human CRC samples. Genetic knockdown of StarD5 (shRNA) (KD) inhibited the CRCSC phenotype in vitrogrowth and self-renewal (1°→3° spheroid formation), CRCSC maker levels, and sensitivity to 5-fluorouracil. Also, StarD5-depleted HT-29 cells showed a robust (40-fold) reduction in tumor formation (CRCSC characteristics) in vivo and CRCSC phenotype ex vivo, including CRCSC marker expression and spheroid formation (1°→3°). StarD5 inhibition also caused a significant increase in apoptosis induction. Mechanistically, PM cholesterol levels were significantly higher in CRCSCs than in non-CRCSCs, and StarD5 depletion decreased accessible PM cholesterol, particularly in specialized lipid raft domains. Finally, cholesterol depletion in the PM is critical for StarD5 KD's inhibition of the CRCSC phenotype as supplementation with low-density lipoprotein caused a significant reversal of the StarD5 KD effects on PM/raft cholesterol levels and CRCSC phenotype. Implications: Given StarD5's critical role in regulation of CRCSCs, translational research targeting StarD5 will lead to improved outcomes in patients with CRC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639159","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

E3 Ubiquitin Ligase ITCH Enhances p53 Ubiquitination-Dependent Degradation and Drives Osteosarcoma Tumorigenesis. E3泛素连接酶ITCH增强p53泛素化依赖性降解并驱动骨肉瘤肿瘤发生。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2026-04-07 DOI: 10.1158/1541-7786.MCR-25-0687

Jin Zeng, Haibo Zhan, Jun Xiao, Fang Huang, Weiguo Bian

{"title":"E3 Ubiquitin Ligase ITCH Enhances p53 Ubiquitination-Dependent Degradation and Drives Osteosarcoma Tumorigenesis.","authors":"Jin Zeng, Haibo Zhan, Jun Xiao, Fang Huang, Weiguo Bian","doi":"10.1158/1541-7786.MCR-25-0687","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0687","url":null,"abstract":"Osteosarcoma (OS) remains a highly aggressive malignant tumor with strong metastatic potential and limited therapeutic options. E3 ubiquitin ligases, particularly the HECT-type family, regulate oncogenic pathways via targeted protein degradation. Among them, ‌Itchy E3 ubiquitin protein ligase (ITCH) has been implicated in poor prognosis in multiple cancers. However, its functional effects and clinical relevance in OS pathogenesis remain completely unexplored. Herein, ITCH expression in OS tissues was detected using qRT-PCR, Western blot, and immunohistochemistry. In vitro and in vivo, the function of ITCH was evaluated by soft agar colony formation assay, Transwell assay, CCK8 assay, wound healing assay, immunofluorescence, flow cytometric analysis, and xenograft tumor assay. Downstream targets were further investigated using proteomic analysis, Western blot, and immunoprecipitation. ITCH aberrantly overexpressed in OS tissues, exhibiting a strong negative correlation with patient survival. Mechanistically, ITCH directly bound P53 and mediated its ubiquitination and degradation. ITCH-driven P53 loss enhanced malignant phenotypes, while ITCH knockdown restored P53 stability. This study demonstrates that ITCH functions as an oncogene in OS by targeting P53 for degradation, and suggests ITCH as a promising therapeutic target. Implications: These findings define a molecular mechanism underlying the oncogenic role of ITCH through P53 ubiquitination-dependent degradation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628158","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

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

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 4.7 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":4.7,"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