Molecular Oncology最新文献

{"title":"CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer.","authors":"Hao-Wei Teng, Hsiang-Yueh Huang, Chun-Chi Lin, Yuh-Ching Twu, Wen-Hao Yang, Wen-Chun Lin, Hsin-Yi Lan, Yen-Yu Lin, Wei-Lun Hwang","doi":"10.1002/1878-0261.13736","DOIUrl":"10.1002/1878-0261.13736","url":null,"abstract":"<p><p>Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival. However, a portion of MSI-H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor-autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI-H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell-in-cell (CIC) structure formation. RNA-sequencing (RNA-seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin-fixed paraffin-embedded (FFPE) MSI-H CRC specimens was performed to explore the underlying mechanisms involved. We showed that cancer/testis antigen family 45 member A1 (CT45A1) expression was upregulated in MSI-H CRC patients with poor survival outcomes. CT45A1-expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability. However, CT45A1-expressing MSI-H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC cells. Inactivating RHO-ROCK/MLCK-MLC2 signaling with small-molecule inhibitors or short-hairpin RNAs (shRNAs) targeting myosin light chain kinase (MYLK) abolished NK cell resistance and reduced the outer cell fate of CT45A1-expressing MSI-H CRC cells. In MSI-H CRC patients, CT45A1-positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival. We demonstrated that CT45A1 potentiates the advanced progression of MSI-H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1-positive MSI-H CRC patients.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"430-451"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350333","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":"Viral mimicry evasion: a new role for oncogenic KRAS mutations.","authors":"Raymond Chen, Aobo He, Daniel D De Carvalho","doi":"10.1002/1878-0261.13771","DOIUrl":"10.1002/1878-0261.13771","url":null,"abstract":"<p><p>\"Viral mimicry\" refers to the induction of an innate immune response and interferon signaling by endogenous stimuli such as double-stranded RNA (dsRNA). This response has been shown to have strong cancer therapeutic potential, including by enhancing the effectiveness of immune checkpoint inhibition (ICI) therapies, and may represent a tumor suppression mechanism that needs to be overcome for malignant transformation to proceed. In a recent study, Zhou and colleagues identify KRAS, a frequently mutated oncogene, as a negative regulator of dsRNA and viral mimicry in an ICI-resistant colorectal cancer model. Oncogenic KRAS^G12D mutations downregulate the RNA-binding protein DDX60 by activating the AKT signaling pathway, which inhibits STAT3, a critical transcription factor regulating DDX60 and other interferon-stimulated genes. Overexpression of DDX60, which competitively binds to dsRNA to prevent RISC-mediated degradation, or targeting of KRAS^G12D elevated dsRNA levels, resulting in viral mimicry activation and potentiation of ICI treatment. These results establish KRAS as a promising target to sensitize immune \"cold\" tumors to ICI therapy and demonstrate the potential role of oncogenic mutations in viral mimicry evasion during tumorigenesis.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"271-274"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730734","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":"Oncogenic mutant KRAS inhibition through oxidation at cysteine 118.","authors":"Maximilian Kramer-Drauberg, Ettore Petrini, Alessia Mira, Enrico Patrucco, Rossella Scardaci, Ilenia Savinelli, Haiyun Wang, Keying Qiao, Giovanna Carrà, Marie-Julie Nokin, Zhiwei Zhou, Kenneth D Westover, David Santamaria, Paolo E Porporato, Chiara Ambrogio","doi":"10.1002/1878-0261.13798","DOIUrl":"10.1002/1878-0261.13798","url":null,"abstract":"<p><p>Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"311-328"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007649","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":"When molecular biology transforms clinical oncology: the EGFR journey in colorectal cancer.","authors":"Pietro Paolo Vitiello, Nadia Saoudi González, Alberto Bardelli","doi":"10.1002/1878-0261.13754","DOIUrl":"10.1002/1878-0261.13754","url":null,"abstract":"<p><p>The discovery of growth factors and their involvement in cancer represents the foundation of precision oncology. The preclinical and clinical development of agents targeting epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) were accompanied by big hype and hopes, though the clinical testing of such agents clashed with intrinsic and acquired resistance, greatly limiting their therapeutic value. However, a better understanding of the biology of the EGFR signaling pathway in CRC, coupled with the development of liquid biopsy methodologies to study cancer evolution in real time, fostered the clinical refinement of anti-EGFR treatment in CRC. Such a workflow, based on the co-evolution of biology knowledge and clinical development, allowed to couple the discovery of relevant therapy resistance mechanisms to the development of strategies to bypass this resistance. A broader application of this paradigm could prove successful and create an effective shortcut between the bench and the bedside for treatment strategies other than targeted therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"267-270"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522465","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":"Functional interaction between receptor tyrosine kinase MET and ETS transcription factors promotes prostate cancer progression.","authors":"Elisa Carouge, Clémence Burnichon, Martin Figeac, Shéhérazade Sebda, Nathalie Vanpouille, Audrey Vinchent, Marie-José Truong, Martine Duterque-Coquillaud, David Tulasne, Anne Chotteau-Lelièvre","doi":"10.1002/1878-0261.13739","DOIUrl":"10.1002/1878-0261.13739","url":null,"abstract":"<p><p>Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"474-495"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391849","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":"Global metabolomic profiling of tumor tissue and paired serum samples to identify biomarkers for response to neoadjuvant FOLFIRINOX treatment of human pancreatic cancer.","authors":"Manoj Amrutkar, Sander Johannes Thorbjørnsen Guttorm, Anette Vefferstad Finstadsveen, Knut Jørgen Labori, Lars Eide, Helge Rootwelt, Katja Benedikte Prestø Elgstøen, Ivar P Gladhaug, Caroline S Verbeke","doi":"10.1002/1878-0261.13759","DOIUrl":"10.1002/1878-0261.13759","url":null,"abstract":"<p><p>Neoadjuvant chemotherapy (NAT) is increasingly used for the treatment of non-metastatic pancreatic ductal adenocarcinoma (PDAC) and is established as a standard of care for borderline resectable and locally advanced PDAC. However, full exploitation of its clinical benefits is limited by the lack of biomarkers that assess treatment response. To address this unmet need, global metabolomic profiling was performed on tumor tissue and paired serum samples from patients with treatment-naïve (TN; n = 18) and neoadjuvant leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX)-treated (NAT; n = 17) PDAC using liquid chromatography mass spectrometry. Differentially abundant metabolites (DAMs) in TN versus NAT groups were identified and their correlation with various clinical parameters was assessed. Metabolomics profiling identified 40 tissue and five serum DAMs in TN versus NAT PDAC. In general, DAMs associated with amino acid and nucleotide metabolism were lower in NAT compared to TN. Four DAMs-3-hydroxybutyric acid (BHB), 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), glycochenodeoxycholate and citrulline-were common to both tissue and serum and showed a similar pattern of differential abundance in both groups. A strong positive correlation was observed between serum carbohydrate 19-9 antigen (CA 19-9) and tissue carnitines (C12, C18, C18:2) and N8-acetylspermidine. The reduction in CA 19-9 following NAT correlated negatively with serum deoxycholate levels, and the latter correlated positively with survival. This study revealed neoadjuvant-chemotherapy-induced changes in metabolic pathways in PDAC, mainly amino acid and nucleotide metabolism, and these correlated with reduced CA 19-9 following neoadjuvant FOLFIRINOX treatment.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"391-411"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639321","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":"Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer-results from the FIRE-4.5 study.","authors":"Susanne Klein-Scory, Alexander Baraniskin, Wolff Schmiegel, Thomas Mika, Roland Schroers, Swantje Held, Kathrin Heinrich, David Tougeron, Dominik P Modest, Ingo Schwaner, Jan Eucker, Rudolf Pihusch, Martina Stauch, Florian Kaiser, Christoph Kahl, Meinolf Karthaus, Christian Müller, Christof Burkart, Sebastian Stintzing, Volker Heinemann","doi":"10.1002/1878-0261.13778","DOIUrl":"10.1002/1878-0261.13778","url":null,"abstract":"<p><p>The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell-free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE-4.5 included mCRC patients with BRAF V600E mutation detected by tissue-based analyses. Liquid biopsies (LBs) were collected at baseline (pre-treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)-certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression-free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild-type patients. Follow-up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild-type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"344-356"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780602","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":"Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.","authors":"Koh Furugaki, Takaaki Fujimura, Narumi Sakaguchi, Yasutaka Watanabe, Ken Uchibori, Eisaku Miyauchi, Hidetoshi Hayashi, Ryohei Katayama, Shigeki Yoshiura","doi":"10.1002/1878-0261.13746","DOIUrl":"10.1002/1878-0261.13746","url":null,"abstract":"<p><p>Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK⁺ non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK⁺ NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"519-539"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378102","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":"MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives.","authors":"Michael Karin, Ju Youn Kim","doi":"10.1002/1878-0261.13685","DOIUrl":"10.1002/1878-0261.13685","url":null,"abstract":"<p><p>Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"275-294"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11793012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317802","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":"Loss of Lkb1 cooperates with Braf^V600E and ultraviolet radiation, increasing melanoma multiplicity and neural-like dedifferentiation.","authors":"Kimberley McGrail, Elena González-Sánchez, Paula Granado-Martínez, Roberto Orsenigo, Yuxin Ding, Berta Ferrer, Javier Hernández-Losa, Iván Ortega, Juan Martín-Caballero, Eva Muñoz-Couselo, Vicente García-Patos, Juan A Recio","doi":"10.1002/1878-0261.13715","DOIUrl":"10.1002/1878-0261.13715","url":null,"abstract":"<p><p>The mechanisms that work alongside BRAF^V600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal Braf^V600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with Braf^V600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with Braf^V600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"329-343"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902352","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}