Molecular Cancer Research最新文献

{"title":"Archetype analysis of lung adenocarcinoma premalignancy links heterogeneity in premalignant lesions to diverging features of invasive disease.","authors":"Kelley E Anderson, Linh M Tran, Kostyantyn Krysan, Yohana Kefella, Lingge Yu, Gregory A Fishbein, Erika F Rodriguez, Maryam Shabihkhani, Daniel P Stefanko, Emily Green, Gang Liu, Hanqiao Liu, Sherry Zhang, Erin Kane, Mitra Mehrad, Avrum E Spira, Steven M Dubinett, Eric J Burks, Sarah A Mazzilli, Marc E Lenburg, Jennifer E Beane","doi":"10.1158/1541-7786.MCR-25-1093","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-1093","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD), the most common form of lung cancer, is a heterogeneous disease with highly variable histopathologic features and clinical outcomes. LUAD premalignant lesions (PMLs) are localized proliferative lesions of atypical pneumocytes that proliferate along the alveolar walls. In this study, we characterized the molecular heterogeneity across PMLs, regardless of histologic designation, and identified four unique groups or \"archetypes\" of PMLs using bulk RNA and exome sequencing data from laser captured microdissected PMLs, normal, and tumor tissue from LUAD resection cases. The archetypes were defined based on expression of recurrent gene co-expression modules discovered using the LUAD PMLs we profiled and three publicly available datasets. One PML archetype, termed \"proliferation\", was associated with increased expression of genes involved in cell proliferation, a pro-tumor immune environment, and enrichment for EGFR driver mutations. Another archetype, termed \"normal-like\", was associated with similar features to normal tissue, an anti-tumor immune response, and lacked enrichment for driver mutations compared to other archetypes. We projected the PML archetypes into independent gene expression datasets profiling LUAD and found that tumors closest to the proliferation archetype were enriched for multiple features of aggressive LUAD, including high tumor grade and lymph node invasion, and had significantly lower disease-free survival. Proliferation archetype PMLs may represent a subset of lesions with more aggressive features that could improve patient stratification and suggest novel targets for lung cancer interception. Implications: Molecular signatures that distinguish indolent from aggressive LUAD PML may help personalize lung cancer screening and interception protocols.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840789","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}

{"title":"Correction: NP-ALT, a Liposomal:Peptide Drug, Blocks p27Kip1 Phosphorylation to Induce Oxidative Stress, Necroptosis, and Regression in Therapy-Resistant Breast Cancer Cells.","authors":"Irina Jilishitz, Jason Luis Quiñones, Priyank Patel, Grace Chen, Jared Pasetsky, Allison VanInwegen, Scott Schoninger, Manasi P Jogalekar, Vladislav Tsiperson, Lingyue Yan, Yun Wu, Susan R S Gottesman, Jonathan Somma, Stacy W Blain","doi":"10.1158/1541-7786.MCR-26-0150","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0150","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 5","pages":"401"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818087","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}

{"title":"Contrasting Features of Papillary and Chromophobe Renal Cell Carcinoma Revealed by Whole-Genome Sequencing.","authors":"Richard Culliford, Charlie Mills, Daniel Chubb, Ben Kinnersley, Amit Sud, Alex J Cornish, Lisa Browning, Samuel E D Lawrence, Robert Bentham, Anna Frangou, Andreas J Gruber, Kevin Litchfield, David C Wedge, James Larkin, Samra Turajlic, Richard S Houlston","doi":"10.1158/1541-7786.MCR-25-0616","DOIUrl":"10.1158/1541-7786.MCR-25-0616","url":null,"abstract":"<p><p>The identification of cancer drivers is a cornerstone to the delivery of precision oncology. So far, sequencing of renal cell cancer (RCC) has largely been confined to the clear cell subtype of RCC. In contrast, sequencing analyses of the less common forms of RCC, papillary RCC (pRCC) and chromophobe RCC (ChRCC), have so far been limited. We analyzed whole-genome sequencing data on 164 tumor-normal pairs from the Genomics England 100,000 Genomes Project, providing a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genomic features, including mutational signatures, intratumor heterogeneity, and analysis of extrachromosomal DNA formation. Our research establishes correlations between genomic alterations and histologic diversification and the extent to which genetically-mediated immune escape contributes to the development of these RCC subtypes.</p><p><strong>Implications: </strong>We demonstrate the distinctive genetics that characterizes pRCC and ChRCC and how this information has the potential to inform patient treatment and clinical trials.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"327-336"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Intraperitoneal Oil Application Causes Local Inflammation with Depletion of Resident Peritoneal Macrophages.","authors":"Elisenda Alsina-Sanchis, Ronja Mülfarth, Iris Moll, Carolin Mogler, Juan Rodriguez-Vita, Andreas Fischer","doi":"10.1158/1541-7786.MCR-26-0291","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0291","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 5","pages":"402"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818073","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}

{"title":"C1QBP-STAT1 Interaction Promotes Activation of the c-Myc-CHK1/CHK2 Signaling Axis and Radioresistance in Lung Cancer.","authors":"Yuting Liu, Juanjuan Wang, Ying Xiong, Min Sun, Chen Tian, Xiaohua Hong, Feifei Gu, Kai Zhang, Yue Hu, Li Liu, Yulan Zeng","doi":"10.1158/1541-7786.MCR-25-0818","DOIUrl":"10.1158/1541-7786.MCR-25-0818","url":null,"abstract":"<p><p>One of the primary factors contributing to the failure of radiotherapy is the resistance of cancer cells to radiation. Identification of the targets of radiation sensitization and exploration of the molecular mechanism of radioresistance are urgently needed. In this study, we demonstrate that the multifunctional chaperone protein component 1Q subcomponent-binding protein (C1QBP) is required for radioresistance and proliferation in lung cancer cells and tissues; C1QBP is significantly overexpressed, indicating poor prognosis. Blocking C1QBP in vivo and in vitro significantly reduces lung cancer proliferation and growth, increasing lung cancer radiosensitivity. In terms of mechanism, we observed that C1QBP interacts with STAT1 and promotes c-Myc-CHK1/CHK2 signaling axis activation. However, STAT1 is necessary for the influence of C1QBP on lung cancer proliferation and radiosensitivity.</p><p><strong>Implications: </strong>These findings establish C1QBP as a key regulator of lung cancer progression and radioresistance, revealing a novel therapeutic avenue for this disease.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"315-326"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125934","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}

{"title":"Non-Clear Cell Renal Cell Carcinoma Has an Immune-Cold Phenotype That Affects Response to Immune Checkpoint Inhibitors.","authors":"Hiroki Ishihara, Yu-Yu Liu, Riu Yamashita, Hironori Fukuda, Yukihiro Mizoguchi, Makiko Yamashita, Shigehisa Kitano, Kazunori Aoki, Hidekazu Tachibana, Shinsuke Mizoguchi, Koichi Nishimura, Takayuki Nakayama, Yuki Nemoto, Kazuhiko Yoshida, Toshihito Hirai, Junpei Iizuka, Yoji Nagashima, Toshikazu Ushijima, Daisuke Tokita, Tsunenori Kondo, Toshio Takagi","doi":"10.1158/1541-7786.MCR-25-0939","DOIUrl":"10.1158/1541-7786.MCR-25-0939","url":null,"abstract":"<p><p>Data on the clinical outcomes of immune checkpoint inhibitor (ICI) therapy and tumor immune microenvironment (TIME) profiles in non-clear cell renal cell carcinoma (nccRCC) remain limited. In this study, we retrospectively compared the effectiveness profile of first-line ICI combination therapy between clear-cell renal cell carcinoma (ccRCC) and nccRCC. Additionally, genome-wide gene expression and tumor-infiltrating immune cell (TIIC) profiling were performed using RNA sequencing and flow cytometry, respectively. Of 266 patients, 56 (21%) were histopathologically diagnosed with nccRCC. Progression-free survival [PFS; hazard ratio (HR), 0.59, P = 0.0059] and overall survival (OS; HR, 0.42, P = 0.0006) were shorter in patients with nccRCC than in patients with ccRCC. Gene expression analysis of 140 RCC samples revealed the downregulation of immune-related and angiogenesis-related pathways in nccRCC. The survival difference between ccRCC and nccRCC was more significant with the combination of ICIs and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI; PFS: HR, 0.45, P = 0.0026; OS: HR, 0.26, P < 0.0001) than with dual ICI combinations (PFS: HR, 0.64, P = 0.0761; OS: HR, 0.59, P = 0.131). TIIC profiling of 116 samples showed that nccRCC exhibited an \"immune-cold\" TIME phenotype characterized by a decrease in TIICs, including CD8+ T cells. In conclusion, the downregulation of immune-related pathways, caused by an \"immune-cold\" TIME phenotype, is potentially involved in the pathogenesis underlying the decrease in the therapeutic efficacy of ICI combination therapy for nccRCC.</p><p><strong>Implications: </strong>nccRCC harbors an \"immune-cold\" TIME phenotype characterized by reduced TIICs, which in turn drive the downregulation of immune-related pathways and may contribute to decreased responsiveness to ICI therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"390-400"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053258","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}

{"title":"Retraction: SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism.","authors":"Bao Hoang, Yijiang Shi, Patrick J Frost, Veena Mysore, Carolyne Bardeleben, Alan Lichtenstein","doi":"10.1158/1541-7786.MCR-26-0310","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0310","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 5","pages":"404"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818090","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}

{"title":"OGDHL Promotes Prostate Cancer Progression and Regulates Neuroendocrine Marker Expression and Nucleotide Abundance.","authors":"Matthew J Bernard, Andrea Gallardo, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Shile Zhang, Ernie Lee, Kylie Y Heering, Grigor Varuzhanyan, Sachi Bopardikar, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Sandy Che-Eun S Lee, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Owen N Witte, Michael C Haffner, David B Shackelford, Paul C Boutros, Heather R Christofk, Andrew S Goldstein","doi":"10.1158/1541-7786.MCR-25-0913","DOIUrl":"10.1158/1541-7786.MCR-25-0913","url":null,"abstract":"<p><p>As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternative metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment resistance. We identify the poorly studied metabolic enzyme oxoglutarate dehydrogenase-like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme oxoglutarate dehydrogenase, as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA damage in prostate cancer. Although OGDHL has been described as a tumor suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker γH2AX, and alters androgen receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine (NE) differentiation in clinical prostate cancer and that knockdown of OGDHL impairs the growth of cell line models of NE prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer.</p><p><strong>Implications: </strong>OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and NE differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"356-375"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOSL2 Regulates PD-L1 and Modulates Hormone Therapy Response Heterogeneity.","authors":"Feifei Sun, Baozhen Wang, Shuyu Mei, Lin Zhang, Xinpei Wang, Hui Liu, Wenyao Liu, Jiajia Wang, Qianqian Zhou, Bo Han, Jing Hu, Lin Gao, Xueli Wang","doi":"10.1158/1541-7786.MCR-25-0611","DOIUrl":"10.1158/1541-7786.MCR-25-0611","url":null,"abstract":"<p><p>The response to androgen-targeted therapy in prostate cancer is highly heterogeneous. Although previous studies have primarily concentrated on tumor cell-intrinsic signaling changes, the tumor microenvironment, particularly the interactions between tumor-infiltrating lymphocytes (TIL) and tumor cells, is equally critical in shaping treatment responses. Building on our previous observations linking TILs to treatment efficacy in the context of neoadjuvant androgen deprivation therapy, we employed publicly available clinical datasets, in vitro T-cell prostate cancer cell coculture systems, and murine xenograft models to investigate this interplay. We found treatment-related dynamic changes in TIL populations, accompanied by a concordant expression pattern of FOSL2 and PD-L1. Mechanistically, FOSL2 directly bound to the PD-L1 promoter to transcriptionally upregulate PD-L1, thereby modulating T-cell infiltration and function. Importantly, in vivo results demonstrated that targeting FOSL2 enhanced the antitumor effect when combined with hormone therapy and anti-PD-L1 treatment. These findings suggest that FOSL2 may contribute to treatment response heterogeneity by shaping the tumor immune microenvironment, offering novel insights into resistance mechanisms and uncovering potential strategies to enhance the efficacy of hormone therapy in prostate cancer.</p><p><strong>Implications: </strong>Targeting FOSL2-mediated PD-L1 regulation offers a promising strategy to overcome immune microenvironment-mediated resistance and improve the therapeutic efficacy of androgen-targeted therapy in prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"376-389"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086320","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}

{"title":"Correction: Dual Inhibition of CDK4 and CDK2 via Targeting p27 Tyrosine Phosphorylation Induces a Potent and Durable Response in Breast Cancer Cells.","authors":"Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain","doi":"10.1158/1541-7786.MCR-26-0146","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0146","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 5","pages":"403"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818078","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}