Molecular Oncology最新文献

{"title":"Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas.","authors":"Amanda Frydendahl, Adam J Widman, Nadia Øgaard, Anushri Arora, Daniel Halmos, Jesper Nors, Johanne Ahrenfeldt, Tenna V Henriksen, Christina Demuth, Line Raaby, Mads H Rasmussen, Christina Therkildsen, Dan A Landau, Claus L Andersen","doi":"10.1002/1878-0261.13803","DOIUrl":"10.1002/1878-0261.13803","url":null,"abstract":"<p><p>The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10-15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGE^SNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGE^SNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10^-5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"984-993"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008044","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 to \"hnRNPA2/B1 activates cyclooxygenase-2 and promotes tumor growth in human lung cancers\".","authors":"","doi":"10.1002/1878-0261.70016","DOIUrl":"10.1002/1878-0261.70016","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1282-1283"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597072","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":"The CDK12-BRCA1 signaling axis mediates dinaciclib-associated radiosensitivity through p53-mediated cellular senescence.","authors":"Natalia García Flores, Diego M Fernández-Aroca, Cristina Garnés-García, Andrés Domínguez-Calvo, Jaime Jiménez-Suárez, Sebastià Sabater, Pablo Fernández-Aroca, Ignacio Andrés, Francisco J Cimas, Guillermo de Cárcer, Borja Belandia, Ignacio Palmero, Pablo Huertas, María José Ruiz-Hidalgo, Ricardo Sánchez-Prieto","doi":"10.1002/1878-0261.13773","DOIUrl":"10.1002/1878-0261.13773","url":null,"abstract":"<p><p>Pan-cyclin-dependent-kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter serine-protein kinase ATM signalling or cell cycle profiling after ionising-radiation exposure, which have been described for other CDK inhibitors. Interestingly, in terms of apoptosis, although the combination renders a clear increase, no potentiation of the ionising-radiation-induced apoptosis was observed. Mechanistically, inhibition of CDK12 by dinaciclib diminishes BRCA1 expression, which decreases homologous recombination (HR) and probably promotes the nonhomologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising-radiation-associated cellular senescence in a TP53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12-BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1265-1280"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770616","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":"Multi-omics profiling reveals key factors involved in Ewing sarcoma metastasis.","authors":"Mariona Chicón-Bosch, Sara Sánchez-Serra, Marta Rosàs-Lapeña, Nicolás Costa-Fraga, Judit Besalú-Velázquez, Janet Illa-Bernadí, Silvia Mateo-Lozano, Florencia Cidre-Aranaz, Thomas G P Grünewald, Ángel Díaz-Lagares, Roser Lopez-Alemany, Òscar M Tirado","doi":"10.1002/1878-0261.13788","DOIUrl":"10.1002/1878-0261.13788","url":null,"abstract":"<p><p>Ewing sarcoma (EWS) is the second most common bone tumor affecting children and young adults, with dismal outcomes for patients with metastasis at diagnosis. Mechanisms leading to metastasis remain poorly understood. To deepen our knowledge on EWS progression, we have profiled tumors and metastases from a spontaneous metastasis mouse model using a multi-omics approach. Combining transcriptomics, proteomics, and methylomics analyses, we identified signaling cascades and candidate genes enriched in metastases that could be modulating aggressiveness in EWS. Phenotypical validation of two of these candidates, cyclic AMP-responsive element-binding protein 1 (CREB1) and lipoxygenase homology domain-containing protein 1 (LOXHD1), showed an association with migration and clonogenic abilities. Moreover, previously described CREB1 downstream targets were present amongst the metastatic-enriched results. Combining the different omics datasets, we identified FYVE, RhoGEF, and PH domain-containing protein 4 (FGD4) as a CREB1 target interconnecting the different EWS biological layers (RNA, protein and methylation status) and whose high expression is associated with worse clinical outcome. Further studies will provide insight into EWS metastasis mechanisms and ultimately improve survival rates for EWS patients.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1002-1028"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932279","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 to \"SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression\".","authors":"","doi":"10.1002/1878-0261.13823","DOIUrl":"10.1002/1878-0261.13823","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1281"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573381","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":"Replenishing co-downregulated miR-100-5p and miR-125b-5p in malignant germ cell tumors causes growth inhibition through cell cycle disruption.","authors":"Marta Ferraresso, Shivani Bailey, Luz Alonso-Crisostomo, Dawn Ward, Christos Panayi, Zachary G L Scurlock, Harpreet K Saini, Stephen P Smith, James C Nicholson, Anton J Enright, Cinzia G Scarpini, Nicholas Coleman, Matthew J Murray","doi":"10.1002/1878-0261.13757","DOIUrl":"10.1002/1878-0261.13757","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are short, nonprotein-coding RNAs, and their expression is dysregulated in malignant germ cell tumors (GCTs). Here, we investigated the causes and consequences of downregulated miR-99a-5p/miR-100-5p (functionally identical) and miR-125b-5p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT-PCR was used to assess miR-99a-5p/miR-100-5p, miR-125b-5p, and associated gene expression in malignant GCT tissues/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5-azacytidine and pyrosequencing was performed. Combination miR-100-5p/miR-125b-5p mimic replenishment was used to treat malignant GCT cells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR-99a-5p/miR-100-5p and miR-125b-5p, their respective pri-miRNAs, and associated genes from chromosomes 11 and 21 (chr11/chr21) were downregulated and highly correlated in malignant GCT cells. Treatment with 5-azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11/chr21 loci, likely contributing to miR-100-5p/miR-125b-5p downregulation. Combination miR-100-5p/miR-125b-5p mimic replenishment resulted in growth inhibition in Sem/YST cells, with miR-100-5p/miR-125b-5p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR-100-5p/miR-125b-5p target tripartite motif containing 71 (TRIM71kd) recapitulated miR-100-5p/miR-125b-5p replenishment, with growth inhibition and cell cycle disruption of Sem/YST/EC cells. Further, replenishment led to reduced lin-28 homolog A (LIN28A) levels and concomitant increases in let-7 (MIRLET7B) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR-100-5p/miR-125b-5p mimic replenishment or TRIM71kd caused growth inhibition in malignant GCT cells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum-based chemotherapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1203-1228"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623841","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":"MicroRNAs in seminal plasma are able to discern infertile men at increased risk of developing testicular cancer.","authors":"Carmen Ferrara, Rosalia Battaglia, Angela Caponnetto, Anna Fazzio, Michele Stella, Cristina Barbagallo, Nicolò Musso, Federica Lunelio, Maria Elena Vento, Placido Borzì, Paolo Scollo, Davide Barbagallo, Marco Ragusa, Salvatore Pernagallo, Cinzia Di Pietro","doi":"10.1002/1878-0261.13784","DOIUrl":"10.1002/1878-0261.13784","url":null,"abstract":"<p><p>Male infertility is a risk factor for the development of testicular germ cell tumors. In this study, we investigated microRNA profiles in seminal plasma to identify potential noninvasive biomarkers able to discriminate the men at highest risk of developing cancer among the infertile population. We compared the microRNA profiles of individuals affected by testicular germ cell tumors and healthy individuals with normal or impaired spermiograms using high-throughput technology and confirmed the results by single-assay digital PCR. We found that miR-221-3p and miR-222-3p were downregulated and miR-126-3p was upregulated in cancer patients compared to both infertile and fertile men. ROC curve analysis confirmed that miR-126 upregulation is able to identify cancer patients among the infertile male population. In addition, in-depth bioinformatics analysis based on weighted gene co-expression networks showed that the identified miRNAs regulate cellular pathways involved in cancer.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1188-1202"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837728","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":"Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal-like and malignant urothelial cells.","authors":"Rebecca M Schlösser, Florian Krumbach, Eyleen Corrales, Geoffroy Andrieux, Christian Preisinger, Franziska Liss, Alexandra Golzmann, Melanie Boerries, Kerstin Becker, Ruth Knüchel, Stefan Garczyk, Bernhard Lüscher","doi":"10.1002/1878-0261.70019","DOIUrl":"https://doi.org/10.1002/1878-0261.70019","url":null,"abstract":"<p><p>Epigenetic regulators, such as the SWI/SNF complex, with important roles in tissue development and homeostasis, are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors; however, the consequences of this remain poorly understood. Finding truncations to be the most common mutation, we generated loss- and gain-of-function models to conduct RNA-Seq, interactome analyses, Omni-ATAC-Seq, and functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways, including DNA repair, in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. ARID1A deficiency drastically reduced the accessibility of chromatin, especially around introns and distal enhancers, in a functional enrichment analysis. Less accessible chromatin areas were mapped to pathways such as cell proliferation and DNA damage response. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, our data highlight the broad impact of ARID1A loss and the possibility of targeting proliferative and DNA repair pathways for treatment.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764461","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":"Unraveling the metastasis-preventing effect of miR-200c in vitro and in vivo.","authors":"Bianca Köhler, Emily Brieger, Tom Brandstätter, Elisa Hörterer, Ulrich Wilk, Jana Pöhmerer, Anna Jötten, Philipp Paulitschke, Chase P Broedersz, Stefan Zahler, Joachim O Rädler, Ernst Wagner, Andreas Roidl","doi":"10.1002/1878-0261.13712","DOIUrl":"10.1002/1878-0261.13712","url":null,"abstract":"<p><p>Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR-200c) can hamper certain steps of the invasion-metastasis cascade. However, it is still unclear whether miR-200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR-200c expression in MDA-MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR-200c-expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR-200c on collective- and single-cell migration in vitro, utilizing MDA-MB 231 and MCF7 cell systems with genetically modified miR-200c expression. Analysis of collective-cell migration revealed confluence-dependent motility of cells with altered miR-200c expression. Additionally, scratch assays showed an enhanced predisposition of miR-200c-negative cells to leave cell clusters. The in-between stage of collective- and single-cell migration was validated using transwell assays, which showed reduced migration of miR-200c-positive cells. Finally, to measure migration at the single-cell level, a novel assay on dumbbell-shaped micropatterns was performed, which revealed that miR-200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR-200c impedes metastasis formation in vivo and migration in vitro and highlights miR-200c as a metastasis suppressor in breast cancer.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1029-1053"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470171","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":"Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer.","authors":"Sang-Min Park, Keeok Haam, Haejeong Heo, Doyeong Kim, Min-Ju Kim, Hyo-Jung Jung, Seongwon Cha, Mirang Kim, Haeseung Lee","doi":"10.1002/1878-0261.13738","DOIUrl":"10.1002/1878-0261.13738","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1155-1169"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623929","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}