Molecular Oncology最新文献

{"title":"Unveiling unique protein and phosphorylation signatures in lung adenocarcinomas with and without ALK, EGFR, and KRAS genetic alterations.","authors":"Fanni Bugyi, Mirjam Balbisi, Simon Sugár, Lóránd Váncza, Eszter Regős, Ilona Kovalszky, Ibolya Laczó, Tünde Harkó, Gábor Kecskeméti, Zoltán Szabó, Judit Moldvay, László Drahos, Lilla Turiák","doi":"10.1002/1878-0261.70091","DOIUrl":"https://doi.org/10.1002/1878-0261.70091","url":null,"abstract":"<p><p>Genetic alterations in key oncogenes have been frequently identified in lung adenocarcinoma (LUAD), including genes encoding epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK). In this pilot study, we aimed to characterize the differences in enriched biological pathways and phosphorylation events between LUAD tumors harboring EGFR, KRAS, or echinoderm microtubule-associated protein-like 4 (EML4)-ALK oncogenic alterations and triple wild-type LUAD tumors (WT, without EML4-ALK, KRAS, or EGFR alterations) by mass spectrometry (MS)-based quantitative proteomics and phosphoproteomics. We analyzed tumor regions of 82 formalin-fixed paraffin-embedded (FFPE) tissue sections with 6, 23, 31, and 22 samples from the EML4-ALK, EGFR, KRAS, and WT sample groups, respectively. A total of 1377 to 2189 proteins and 73 to 1781 phosphosites were quantified in these analyses. Based on the results, the samples clustered according to their genetic alteration type, and EGFR-mutated samples showed unique protein expression patterns. Membrane organization, vesicle organization, and vesicle-mediated transport Gene Ontology Biological Process (GOBP) terms were significantly downregulated in EGFR-mutated samples compared to the other sample groups. Changes in 36 proteins and 52 phosphosites were also identified as potentially specific to a given genetic alteration. Many of these proteins have previously been linked to EGFR or KRAS mutations [e.g., cathepsin L, stimulator of interferon genes protein (STING)], whereas several phosphoproteins are associated with RNA splicing [e.g., serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, and SRSF7 proteins]. Kinase-substrate enrichment analysis indicated altered activities of 10 kinases, including mitogen-activated protein kinases (MAPKs) and cyclin-dependent kinases (CDKs). For example, CDK2 activity was elevated in EML4-ALK samples compared to the other sample groups. Our results could provide significant insights into further studies that could contribute to developing improved diagnostic and therapeutic strategies for LUAD.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575920","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 \"The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma\".","authors":"","doi":"10.1002/1878-0261.70088","DOIUrl":"https://doi.org/10.1002/1878-0261.70088","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553992","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":"Surfaceome: a new era in the discovery of immune evasion mechanisms of circulating tumor cells.","authors":"Doryan Masmoudi, Jérome Vialaret, Christophe Hirtz, Catherine Alix-Panabières","doi":"10.1002/1878-0261.13665","DOIUrl":"10.1002/1878-0261.13665","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs) are cancer cells that detach from the original site and reach the bloodstream. The most aggressive CTCs survive various immune system attacks and initiate metastasis formation. Importantly, CTCs are not specifically targeted by the current immunotherapies due to the limited knowledge on specific targets. Proteomic profiling can be a powerful tool for understanding some of the immune evasion mechanisms used by cancer cells and particularly CTCs. These mechanisms are generally linked to the expression of specific surface proteins/peptides (i.e. the surfaceome). The study of the peptides that bind to class I molecules of the major histocompatibility complex (MHC-I) and of the various glycoproteins expressed on CTC surface may open a completely new avenue for the discovery of novel mechanisms of immune evasion. In this review, we discuss how immunopeptidomic and glycoproteomic studies of CTCs that interact with immune cells could help to better understand how metastasis-initiator CTCs escape the host immune response. We also describe how immunopeptidomic and glycoproteomic studies are carried out.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1979-1997"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076258","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":"Cellular liquid biopsy provides unique chances for disease monitoring, preclinical model generation and therapy adjustment in rare salivary gland cancer patients.","authors":"Nataša Stojanović Gužvić, Florian Lüke, Steffi Treitschke, Andrea Coluccio, Martin Hoffmann, Giancarlo Feliciello, Adithi Ravikumar Varadarajan, Xin Lu, Kathrin Weidele, Catherine Botteron, Silvia Materna-Reichelt, Felix Keil, Katja Evert, Florian Weber, Thomas Schamberger, Michael Althammer, Jirka Grosse, Dirk Hellwig, Christian Schulz, Stephan Seitz, Peter Ugocsai, Anke Schlenska-Lange, Roman Mayr, Ulrich Kaiser, Wolfgang Dietmaier, Bernhard Polzer, Jens Warfsmann, Kamran Honarnejad, Tobias Pukrop, Daniel Heudobler, Christoph A Klein, Christian Werno","doi":"10.1002/1878-0261.13741","DOIUrl":"10.1002/1878-0261.13741","url":null,"abstract":"<p><p>While cell-free liquid biopsy (cfLB) approaches provide simple and inexpensive disease monitoring, cell-based liquid biopsy (cLB) may enable additional molecular genetic assessment of systemic disease heterogeneity and preclinical model development. We investigated 71 blood samples of 62 patients with various advanced cancer types and subjected enriched circulating tumor cells (CTCs) to organoid culture conditions. CTC-derived tumoroid models were characterized by DNA/RNA sequencing and immunohistochemistry, as well as functional drug testing. Results were linked to molecular features of primary tumors, metastases, and CTCs; CTC enumeration was linked to disease progression. Of 52 samples with positive CTC counts (≥1) from eight different cancer types, only CTCs from two salivary gland cancer (SGC) patients formed tumoroid cultures (P = 0.0005). Longitudinal CTC enumeration of one SGC patient closely reflected disease progression during treatment and revealed metastatic relapse earlier than clinical imaging. Multiomics analysis and functional in vitro drug testing identified potential resistance mechanisms and drug vulnerabilities. We conclude that cLB might add a functional dimension (to the genetic approaches) in the personalized management of rare, difficult-to-treat cancers such as SGC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2056-2073"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375636","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":"Integrative analysis of circulating tumor cells (CTCs) and exosomes from small-cell lung cancer (SCLC) patients: a comprehensive approach.","authors":"Dimitrios Papakonstantinou, Argyro Roumeliotou, Evangelia Pantazaka, Athanasios-Nasir Shaukat, Athina Christopoulou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Vassilis Georgoulias, Anastasia Xagara, Evangelia Chantzara, Fillipos Koinis, Athanasios Kotsakis, Constantinos Stathopoulos, Galatea Kallergi","doi":"10.1002/1878-0261.13765","DOIUrl":"10.1002/1878-0261.13765","url":null,"abstract":"<p><p>The increased metastatic ability of small-cell lung cancer (SCLC) necessitates the identification of new prognostic biomarkers for clinical evaluation during the disease course. Our previous research highlighted the clinical relevance of transcription factor JunB (JUNB), C-X-C chemokine receptor type 4 (CXCR4), and programmed cell death 1 ligand 1 (PD-L1) in breast and non-small cell lung cancer (NSCLC) patients. In the current study, we examined these biomarkers in circulating tumor cells (CTCs) and plasma-derived exosomes from 100 treatment-naïve SCLC patients. CTCs were analyzed using the VyCAP system, whereas exosomes were characterized molecularly and transcriptomically. JUNB, CXCR4, and PD-L1 were highly prevalent in CTCs. Patients exhibited significantly increased protein exosomal expression of JUNB and CXCR4 compared to healthy individuals. Overexpression of JUNB and CXCR4 in exosomes can distinguish patients from normal donors, offering an interesting tool for early diagnosis. The presence of JUNB and/or CXCR4 in CTCs correlated with significantly poorer overall survival. CXCR4 exosomal overexpression was associated with CTC presence and their phenotypes. Conclusively, a comprehensive analysis of CTCs and exosomes provides useful prognostic and potential diagnostic tools for SCLC patients.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2038-2055"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687725","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":"Unlocking the potential of tumor-derived DNA in urine for cancer detection: methodological challenges and opportunities.","authors":"Birgit M M Wever, Renske D M Steenbergen","doi":"10.1002/1878-0261.13628","DOIUrl":"10.1002/1878-0261.13628","url":null,"abstract":"<p><p>High cancer mortality rates and the rising cancer burden worldwide drive the development of innovative methods in order to advance cancer diagnostics. Urine contains a viable source of tumor material and allows for self-collection from home. Biomarker testing in this liquid biopsy represents a novel approach that is convenient for patients and can be effective in detecting cancer at a curable stage. Here, we set out to provide a detailed overview of the rationale behind urine-based cancer detection, with a focus on non-urological cancers, and its potential for cancer diagnostics. Moreover, evolving methodological challenges and untapped opportunities for urine biomarker testing are discussed, particularly emphasizing DNA methylation of tumor-derived cell-free DNA. We also provide future recommendations for technical advancements in urine-based cancer detection and elaborate on potential mechanisms involved in the transrenal transport of cell-free DNA.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1918-1934"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094319","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":"Cell-free and extracellular vesicle microRNAs with clinical utility for solid tumors.","authors":"Yoshinori Hayashi, Janelle-Cheri Millen, Romela Irene Ramos, Jennifer A Linehan, Timothy G Wilson, Dave S B Hoon, Matias A Bustos","doi":"10.1002/1878-0261.13709","DOIUrl":"10.1002/1878-0261.13709","url":null,"abstract":"<p><p>As cutting-edge technologies applied for the study of body fluid molecular biomarkers are continuously evolving, clinical applications of these biomarkers improve. Diverse forms of circulating molecular biomarkers have been described, including cell-free DNA (cfDNA), circulating tumor cells (CTCs), and cell-free microRNAs (cfmiRs), although unresolved issues remain in their applicability, specificity, sensitivity, and reproducibility. Translational studies demonstrating the clinical utility and importance of cfmiRs in multiple cancers have significantly increased. This review aims to summarize the last 5 years of translational cancer research in the field of cfmiRs and their potential clinical applications to diagnosis, prognosis, and monitoring disease recurrence or treatment responses with a focus on solid tumors. PubMed was utilized for the literature search, following rigorous exclusion criteria for studies based on tumor types, patient sample size, and clinical applications. A total of 136 studies on cfmiRs in different solid tumors were identified and divided based on tumor types, organ sites, number of cfmiRs found, methodology, and types of biofluids analyzed. This comprehensive review emphasizes clinical applications of cfmiRs and summarizes underserved areas where more research and validations are needed.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1935-1967"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917125","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":"Detection rate for ESR1 mutations is higher in circulating-tumor-cell-derived genomic DNA than in paired plasma cell-free DNA samples as revealed by ddPCR.","authors":"Stavroula Smilkou, Aliki Ntzifa, Victoria Tserpeli, Ioanna Balgkouranidou, Alkistis Papatheodoridi, Evangelia Razis, Helena Linardou, Christos Papadimitriou, Amanda Psyrri, Flora Zagouri, Stylianos Kakolyris, Evi Lianidou","doi":"10.1002/1878-0261.13787","DOIUrl":"10.1002/1878-0261.13787","url":null,"abstract":"<p><p>Plasma cell-free DNA (cfDNA) analysis to track estrogen receptor 1 (ESR1) mutations is highly beneficial for the identification of tumor molecular dynamics and the improvement of personalized treatments for patients with metastatic breast cancer (MBC). Plasma-cfDNA is, up to now, the most frequent liquid biopsy analyte used to evaluate ESR1 mutational status. Circulating tumor cell (CTC) enumeration and molecular characterization analysis provides important clinical information in patients with MBC. In this study, we investigated whether analysis of CTCs and circulating tumor DNA (ctDNA) provide similar or complementary information for the analysis of ESR1 mutations. We analyzed both plasma-cfDNA (n = 90) and paired CTC-derived genomic DNA (gDNA; n = 42) from 90 MBC patients for seven ESR1 mutations. Eight out of 90 (8.9%) plasma-cfDNA samples tested using the ddPLEX Mutation Detection Assay (Bio-Rad, Hercules, CA, USA), were found positive for one ESR1 mutation, whereas 11/42 (26.2%) CTC-derived gDNA samples were found positive for at least one ESR1 mutation. Direct comparison of paired samples (n = 42) revealed that the ESR1 mutation rate was higher in CTC-derived gDNA (11/42, 26.2%) than in plasma-cfDNA (6/42, 14.3%) samples. Our results, using this highly sensitive ddPLEX assay, reveal a higher percentage of mutations in CTC-derived gDNAs than in paired ctDNA in patients with MBC. CTC-derived gDNA analysis should be further evaluated as an important and complementary tool to ctDNA for identifying patients with ESR1 mutations and for guiding individualized therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2109-2119"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927618","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":"Circulating tumor cells in metastatic breast cancer patients treated with immune checkpoint inhibitors - a biomarker analysis of the ALICE and ICON trials.","authors":"Nikolai Kragøe Andresen, Andreas Hagen Røssevold, Elin Borgen, Cecilie Bendigtsen Schirmer, Bjørnar Gilje, Øystein Garred, Jon Lømo, Marius Stensland, Oddmund Nordgård, Ragnhild Sørum Falk, Randi R Mathiesen, Hege G Russnes, Jon Amund Kyte, Bjørn Naume","doi":"10.1002/1878-0261.13675","DOIUrl":"10.1002/1878-0261.13675","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have been introduced in breast cancer (BC) treatment and better biomarkers are needed to predict benefit. Circulating tumor cells (CTCs) are prognostic in BC, but knowledge is limited on CTCs in the context of ICI therapy. In this study, serial sampling of CTCs (CellSearch system) was evaluated in 82 patients with metastatic BC enrolled in two randomized trials investigating ICI plus chemotherapy. Programmed death-ligand 1 (PD-L1) expression on CTCs was also measured. Patients with ≥ 2 CTCs per 7.5 mL at baseline had gene expression profiles in tumor suggestive of increased T-cell activity, including increased tumor inflammation signature (TIS) in both triple-negative (P = 0.010) and hormone receptor-positive (P = 0.024) disease. Patients with luminal A BC had higher CTC levels. The association between CTC status and outcome was most apparent 4 weeks into therapy. PD-L1 expression in CTCs was observed in 6/17 CTC-positive patients and was associated with inferior survival. In conclusion, our study indicates that CTC numbers may inform on tumor immune composition, as well as prognosis. These findings suggest a potential of using CTCs as an accessible biomarker source in BC patients treated with immunotherapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2092-2108"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559176","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":"Circulating tumor DNA (ctDNA) trajectories predict survival in trifluridine/tipiracil-treated metastatic colorectal cancer patients.","authors":"Matthias Unseld, Stefan Kühberger, Ricarda Graf, Christine Beichler, Markus Braun, Nadia Dandachi, Ellen Heitzer, Gerald W Prager","doi":"10.1002/1878-0261.13755","DOIUrl":"10.1002/1878-0261.13755","url":null,"abstract":"<p><p>Late-line treatment in metastatic colorectal cancer (mCRC) can improve prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. We investigated the prognostic role of circulating tumor DNA (ctDNA) in mCRC patients before and during treatment with trifluridine/tipiracil (FTD/TPI). This noninterventional translational biomarker phase II study enrolled 30 mCRC patients (60% male, 40% female). Using a 77-gene panel, ctDNA was detectable in 90% of patients. Tumor levels were assessed based on aneuploidy (ichorCNA) as well as the highest variant allele frequency, and correlated with overall survival (OS). Uni- and multivariate survival analyses were performed with clinical variables. Longitudinal changes in tumor levels over time were analyzed with linear mixed and joint models. The median OS was 8.1 months, with a recorded disease control rate of 30%. High ctDNA levels (≥ 5%) were associated with inferior survival after undergoing FTD/TPI therapy. Elevated tumor level trajectories over time were associated with higher risks of death. Therefore, ctDNA can help identify patients who are unlikely to benefit significantly from this treatment in late-stage disease, thus preventing unnecessary treatments and their associated side effects, ultimately enhancing quality of life.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2120-2132"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008615","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}