Molecular Oncology最新文献

{"title":"Small modifier, big decision: switching to SUMO mode adds weight to cancer stemness in mammary tumors.","authors":"Veronika Yevdokimova, Yannick D Benoit","doi":"10.1002/1878-0261.70082","DOIUrl":"10.1002/1878-0261.70082","url":null,"abstract":"<p><p>Protein SUMOylation is crucial for maintaining the hallmarks of cancer stem cells, including self-renewal and active pluripotency gene networks. While inhibiting key steps of the SUMOylation cascade has been shown to suppress tumorigenesis, the specific mechanisms of SUMO dependency in cancer have not been comprehensively characterized. Li et al. applied genetically engineered models of mammary gland tumorigenesis to demonstrate that SUMOylation of the transcription factor Etv1 is essential for maintaining cancer stem cell functions. Moreover, SUMO conjugation of Etv1 acts as a switch between stem and nonstem cancer cell states. Here, we discuss the implications of these findings regarding the role of SUMOylation-dependent mechanisms in the hierarchical organization of malignant cells and intratumor heterogeneity and highlight potential therapeutic approaches harnessing the SUMOylation cascade.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2166-2170"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369076","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":"Ubiquitination of transcription factors in cancer: unveiling therapeutic potential.","authors":"Dongha Kim, Hye Jin Nam, Sung Hee Baek","doi":"10.1002/1878-0261.70033","DOIUrl":"10.1002/1878-0261.70033","url":null,"abstract":"<p><p>Transcription factors, pivotal in gene expression regulation, are essential in cancer progression. Their function is meticulously regulated by post-translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the function of transcription factors, contingent on the context. In cancers, dysregulated ubiquitination of transcription factors contributes to the hallmark of uncontrolled growth and survival of tumors. For example, tumor suppressors such as p53 might be degraded prematurely due to abnormal ubiquitination, causing genomic instability. On the other hand, oncogenic transcription factors may gain stability via ubiquitination, thus facilitating tumorigenesis. Targeting the ubiquitin-proteasome system (UPS) therefore could be a viable therapeutic approach in cancer. Emerging treatments aim to block the ubiquitination of oncogenic transcription factors or to stabilize tumor suppressors. This review underscores the critical impact of transcription factor-altered ubiquitination on cancer progression. Additionally, it outlines innovative therapeutic approaches that involve inhibitors or drugs directed at specific ubiquitin E3 ligases and deubiquitinases (DUBs) that regulate transcription factor activity.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2174-2195"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971669","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":"Targeting the MDM2-MDM4 interaction interface reveals an otherwise therapeutically active wild-type p53 in colorectal cancer.","authors":"Sonia Valentini, Giada Mele, Marika Attili, Maria Rita Assenza, Fulvio Saccoccia, Francesca Sardina, Cinzia Rinaldo, Roberto Massari, Nicola Tirelli, Alfredo Pontecorvi, Fabiola Moretti","doi":"10.1002/1878-0261.70006","DOIUrl":"10.1002/1878-0261.70006","url":null,"abstract":"<p><p>Targeting the heterodimer MDM2/MDM4 is a novel and effective route for the reactivation of wild-type p53 in human tumors with reduced toxicity in nontransformed cells. To improve the therapeutic potential of peptides that interfere with MDM4 binding to MDM2, we demonstrated the tumor-suppressive activity of a short peptide (Pep3S), which is composed of the last five amino acids of the MDM4 protein. Compared to longer peptides (previously identified), Pep3S binds MDM2 with high affinity, increases p53-dependent cell death in 2D and 3D colorectal cancer models, and is more efficacious in suppressing xenograft tumor growth. Furthermore, its encapsulation in poly (lactic-co-glycolic acid) (PLGA) nanoparticles potentiated and prolonged its activity. A p53-specific target gene array revealed an uncommon p53 signature, with Pep3S leading to p53-mediated repression of a subset of p53 targets. Comparative analysis indicated that this repression is driven by p53-mediated activation of miR-34a, which is functional in Pep3S-induced cell death. Of note, unlike other p53-reactivating molecules, Pep3S led to significant downregulation of the cell cycle inhibitor CDKN1A/p21, one of the best-characterized p53-targets. Genetic manipulation of MDM4 demonstrated the requirement of the dissociated protein for p21 downregulation, whereas the miR-34a signature was not altered. At odds with Nutlin-3a, the proliferation status of nontumor muscle and lymphoblastoid cells was not altered by Pep3S. These data indicate that targeting the MDM2/MDM4 interaction region provides a different route for wild-type p53 reactivation in human tumors, potentially reducing toxicity to proliferating nontumor tissue. The development of a PLGA/Pep3S formulation represents a promising approach for therapeutic purposes.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2412-2430"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531639","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":"Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade.","authors":"Tullia C Bruno, Anthony R Cillo","doi":"10.1002/1878-0261.70076","DOIUrl":"10.1002/1878-0261.70076","url":null,"abstract":"<p><p>Combination immunotherapies have entered the treatment armamentarium of oncology, but important knowledge gaps remain in our understanding of how these therapeutics work. A recent study by Rolig, Peng, and colleagues has shed new light on how dual blockade of PD1 and LAG3 enhances antitumor immunity. The authors first interrogated LAG3 expression on T cells across murine tumor models, classifying the models as LAG3^hi or LAG3^lo. Next, they found that LAG3^hi models were unresponsive to anti-PD1 alone but responsive to combination therapy with anti-PD1 + anti-LAG3. Surprisingly, the response to anti-PD1 + anti-LAG3 in LAG3^hi models was associated with reprogramming of CD4⁺ regulatory T cells (Treg) from the canonically immunosuppressive state to an inflammatory state characterized by loss of expression of the transcription factor Foxp3 and upregulation of transcription factor Tbet. Importantly, an analogous reprogrammed Treg state was associated with response to anti-PD1 + anti-LAG3 and longer overall survival in patients with metastatic melanoma. This work highlights the importance of cells beyond cytotoxic CD8⁺ T cells as drivers of response to immunotherapy and sets the stage for subsequent mechanistic and translational studies.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2163-2165"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302516","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":"Does Porphyromonas gingivalis truly inhibit the oral carcinogenesis?","authors":"Chen-Xi Li, Zhong-Cheng Gong","doi":"10.1002/1878-0261.70037","DOIUrl":"10.1002/1878-0261.70037","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2171-2173"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982383","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":"Exploration of heterogeneity and recurrence signatures in hepatocellular carcinoma.","authors":"Wen-Jing Wu, Jianchao Wang, Fuqing Chen, Xuefeng Wang, Bin Lan, Ruyi Fu, Hong Wen, Fangfang Chen, Wei Hong, Tian-Yu Tang, Ying He, Gang Chen, Jianyin Zhou, Hai-Long Piao, Di Chen, Shu-Yong Lin","doi":"10.1002/1878-0261.70012","DOIUrl":"10.1002/1878-0261.70012","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), the sixth most prevalent cancer globally, is characterized by high recurrence rates and poor prognosis. Investigating the heterogeneity of relapsed HCC and identifying key therapeutic targets may facilitate the design of effective anticancer therapies. In this study, integrative analysis of single-cell RNA sequencing data of primary and early-relapsed HCC revealed increased proportions of infiltrating CD8⁺ T cells along with malignant cells and a decrease in CD4⁺ T cells in relapsed HCC. Cellular interaction and immunohistochemical analysis proposed MIF-(CD74 + CXCR4) signaling pathway as a key mechanism by which malignant cells influence immune cells within the tumor microenvironment. Notably, primary malignant cells showed greater differentiation and proliferation potential, whereas relapsed cells exhibited enhanced epithelial-mesenchymal transition and inflammation, along with upregulated glycogen synthesis and metabolism-related gene expression. Using machine learning techniques on bulk RNA-seq data, we developed a relapsed tumor cell-related risk score (RTRS) that independently predicts overall and recurrence-free survival time with higher accuracy compared with conventional clinical variables. Prognostic biomarkers and potential therapeutic targets were validated via RT-qPCR using mouse implantation models. This comprehensive investigation elucidates the heterogeneity of relapsed HCC and constructs a novel postoperative recurrence prognostic model, paving the way for targeted therapies and improved patient outcomes.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2388-2411"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523809","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":"Adverse prognosis gene expression patterns in metastatic castration-resistant prostate cancer.","authors":"Marina N Sharifi, Eric Feng, Nicholas R Rydzewski, Amy K Taylor, Jamie M Sperger, Yue Shi, Kyle T Helzer, Matthew L Bootsma, Viridiana Carreno, Alex H Chang, Luke A Nunamaker, Grace C Blitzer, Tianfu Andy Shang, Aishwarya Subramanian, Anders Bjartell, Andreas Josefsson, Pernilla Wikström, Emily Feng, Manish Kohli, Rendong Yang, Scott M Dehm, Eric J Small, Rahul Aggarwal, David A Quigley, Joshua M Lang, Shuang G Zhao, Martin Sjöström","doi":"10.1002/1878-0261.70001","DOIUrl":"10.1002/1878-0261.70001","url":null,"abstract":"<p><p>Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2348-2365"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476758","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":"RETRACTION: lncRNA-PDPK2P Promotes Hepatocellular Carcinoma Progression Through the PDK1/AKT/Caspase 3 Pathway.","authors":"","doi":"10.1002/1878-0261.70044","DOIUrl":"10.1002/1878-0261.70044","url":null,"abstract":"<p><strong>Retraction: </strong>W. Pan, W. Li, J. Zhao, Z. Huang, J. Zhao, S. Chen, C. Wang, Y. Xue, F. Huang, Q. Fang, J. Wang, D. Brand, and S. G. Zheng, \"lncRNA-PDPK2P Promotes Hepatocellular Carcinoma Progression Through the PDK1/AKT/Caspase 3 Pathway,\" Molecular Oncology 13, no. 10 (2019): 2246-2258, https://doi.org/10.1002/1878-0261.12553. The above article, published online on 01 August 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. A third party reported to the journal that the one of the P-PDPK2P tumor images in Figure 2E appeared to exceed 2 cm in diameter, which exceeds the maximum size recommended by ARRIVE guidelines. Further investigation by the journal and the publisher also found evidence that the second and third P-NC mice in Figures 2E and 2F appeared to be the same mouse, although both were reported as having received different treatments. The authors responded to an inquiry by the publisher and provided original data. An evaluation of these data by the publisher further determined that there were several discrepancies between what was shown in the original data and what was reported in the published article. The authors stated that no mice had been reused between the images in Figures 2E and 2F. The authors also confirmed that one tumor image in Figure 2E exceeded 2 cm, but that the research was performed at the Third Affiliated Hospital at the Sun Yat-sen University and was in compliance with China's \"Guideline for Welfare and Ethical Review of Laboratory Animals\" (GB/T 35892-2018), which sets no tumor diameter limits for nude mice. The parties have determined that the authors violated ARRIVE guidelines governing the maximum size of tumor samples, which had been adopted by the journal at the time of submission. The parties have also determined that there is overwhelming evidence that two mouse subjects were reused in Figures 2E and 2F but were presented as having received different treatments. There were several other discrepancies between the original data provided by the authors and those presented in the published article. The retraction has been agreed to because the article did not conform to the ethical guidelines of the journal at the time of submission and because there is significant evidence that some data included in the article were inaccurate or misreported, which fundamentally compromises the editors' confidence in the conclusions presented. The authors did not indicate their agreement with the retraction.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2458"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002015","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":"Time, the final frontier.","authors":"Gautier Follain, Michal Dibus, Omkar Joshi, Guillaume Jacquemet","doi":"10.1002/1878-0261.70025","DOIUrl":"10.1002/1878-0261.70025","url":null,"abstract":"<p><p>Cancer's notorious heterogeneity poses significant challenges, as each tumor comprises a unique ecosystem. While single-cell and spatial transcriptomics advancements have transformed our understanding of spatial diversity within tumors, the temporal dimension remains underexplored. Tumors are dynamic entities that continuously evolve and adapt, and relying solely on static snapshots obscures the intricate interplay between cancer cells and their microenvironment. Here, we advocate for integrating temporal dynamics into cancer research, emphasizing a fundamental shift from traditional endpoint experiments to data-driven, continuous approaches. This integration involves, for instance, the development of advanced live imaging techniques, innovative temporal omics methodologies, and novel computational tools.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2157-2162"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692804","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":"MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation.","authors":"Célia Guérin, Audrey Vinchent, Marie Fernandes, Isabelle Damour, Agathe Laratte, Rémi Tellier, Gabriella O Estevam, Jean-Pascal Meneboo, Céline Villenet, Clotilde Descarpentries, James S Fraser, Martin Figeac, Alexis B Cortot, Etienne Rouleau, David Tulasne","doi":"10.1002/1878-0261.13806","DOIUrl":"10.1002/1878-0261.13806","url":null,"abstract":"<p><p>In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small-cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2366-2387"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468749","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}