Molecular Cancer最新文献

{"title":"Lactate accumulation induces H4K12la to activate super-enhancer-driven RAD23A expression and promote niraparib resistance in ovarian cancer","authors":"Bingfeng Lu, Shuo Chen, Xue Guan, Xi Chen, Yuping Du, Jing Yuan, Jielin Wang, Qinghua Wu, Lingfeng Zhou, Xiangchun Huang, Yang Zhao","doi":"10.1186/s12943-025-02295-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02295-w","url":null,"abstract":"Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"55 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Loss of vinculin and membrane-bound β-catenin promotes metastasis and predicts poor prognosis in colorectal cancer","authors":"Ting Li, Hanqing Guo, Ying Song, Xiaodi Zhao, Yongquan Shi, Yuanyuan Lu, Sijun Hu, Yongzhan Nie, Daiming Fan, Kaichun Wu","doi":"10.1186/s12943-025-02304-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02304-y","url":null,"abstract":"<p><b>Retraction note: </b><b><i>Mol Cancer</i></b><b>13, 263 (2014)</b></p><p><b>https://doi.org/10.1186/1476-4598-13-263</b></p><p>The Editor-in-Chief and the Publisher have retracted this article. Ten instances of apparent image duplication, some with rotation and contrast changes, were found within and across Figs. 2 and 3, and 6. An investigation by the publisher confirmed several image integrity issues, including but not limited to the reuse of control and figures appearing to overlap after apparent rotation or resizing. Therefore, the Editor-in-Chief no longer has confidence in the results and conclusions of this article.</p><p>Authors Sijun Hu and Yuanyuan Lu could not be contacted by the Publisher. The remaining Authors have not responded to correspondence regarding this retraction.</p><span>Author notes</span><ol><li><p>Ting Li and Hanqing Guo equal contributors.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Gastroenterology & State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China</p><p>Ting Li, Xiaodi Zhao, Yongquan Shi, Yuanyuan Lu, Sijun Hu, Yongzhan Nie, Daiming Fan & Kaichun Wu</p></li><li><p>Department of Gastroenterology, College of Medicine, Xi’an Central Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, China</p><p>Hanqing Guo & Ying Song</p></li></ol><span>Authors</span><ol><li><span>Ting Li</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hanqing Guo</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Ying Song</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaodi Zhao</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yongquan Shi</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yuanyuan Lu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Sijun Hu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yongzhan Nie</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Daiming Fan</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Kaichun Wu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>G","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"61 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage polarity and prognostic indicators","authors":"Xinming Su, Chenhao Liang, Ruixiu Chen, Shiwei Duan","doi":"10.1186/s12943-025-02301-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02301-1","url":null,"abstract":"<p><b>Correction: Mol Cancer 23</b>,<b> 13 (2024)</b></p><p><b>https://doi.org/10.1186/s12943-023-01931-7</b></p><p>Following the publication of the original article [1], the authors realized that they used incorrect word when describing Fig. 1 in its caption, as follows: “A low CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. “. To rectify this error, they have prepared the correct versions as follows: “A high CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis.”. The incorrect and correct Fig. 1 caption are provided below.</p><p> Incorrect Fig. 1 caption:</p><p> CXCL9:SPP1 polarity as an indicator of TME immune activity and prognosis in cancer patients. The CXCL9:SPP1 polarity could serve as an indicator of immune activity within the TME and may hold significance for patient prognosis. A low CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. Conversely, a low CXCL9:SPP1 ratio characterizing TAM polarity indicates the prevalence of immunosuppressive and tumor-promoting factors within the TME, correlating with a poorer prognosis. CXCL9:SPP1, CXCL9 and SPP1; TAMs, tumor-associated macrophages; TME, tumor microenvironment.</p><p> Correct Fig. 1 caption:</p><p> CXCL9:SPP1 polarity as an indicator of TME immune activity and prognosis in cancer patients. The CXCL9:SPP1 polarity could serve as an indicator of immune activity within the TME and may hold significance for patient prognosis. A high CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. Conversely, a low CXCL9:SPP1 ratio characterizing TAM polarity indicates the prevalence of immunosuppressive and tumor-promoting factors within the TME, correlating with a poorer prognosis. CXCL9:SPP1, CXCL9 and SPP1; TAMs, tumor-associated macrophages; TME, tumor microenvironment.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Su X, Liang C, Chen R, et al. Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage Polarity and prognostic indicators. Mol Cancer. 2024;23:13. https://doi.org/10.1186/s12943-023-01931-7.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China</p><p>Xinming Su, Chenhao Lia","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"9 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shifting landscapes of gender equity in oncology journals: a decade of authorship trends","authors":"Hang Yi, Mingzhong Wan, Xu Ou-Yang, Yang Wang, Yan Wang, Yinyan Gao, Qihao Leng, Shuangping Zhang, Yousheng Mao, Guochao Zhang","doi":"10.1186/s12943-025-02286-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02286-x","url":null,"abstract":"Gender disparities persist in academic oncology, particularly in authorship and senior academic roles. This study evaluates trends in authorship gender representation over the past decade across top oncology journals, focusing on regional, journal-specific, and citation-based disparities. A cross-sectional analysis was conducted on 29,005 articles published between 2014 and 2023 in the top 20 oncology journals, identified through the Web of Science database. Author gender was determined using the NamSor tool. Temporal trends were analyzed using linear regression, and multivariate logistic regression identified factors contributing to gender disparities. Regional and citation analyses explored geographic variations and citation count differences. Among analyzed articles, 41.81% of first authors and 29.93% of last authors were female. Female first authorship showed a significant upward trend (P < 0.01), with gender parity projected by 2034, while parity for last authors is expected by 2055. Regional differences were notable, with North America and Europe leading in female representation. Certain journals, such as CA: A Cancer Journal for Clinicians and Molecular Cancer, exhibited higher female authorship proportions, while Journal of Clinical Oncology had the lowest. Citation analysis revealed female-authored articles received significantly fewer citations than male-authored ones (P < 0.01). Although female authorship in oncology journals has increased over the past decade, disparities remain, particularly in senior roles and citation impact. Addressing these issues requires targeted strategies, including mentorship programs, greater female representation in editorial boards, and institutional policies promoting gender equity.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"42 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"o8G-modified circPLCE1 inhibits lung cancer progression via chaperone-mediated autophagy","authors":"Qingyun Zhao, Dunyu Cai, Haotian Xu, Yihong Gao, Ruirui Zhang, Xiaodong Zhou, Xingcai Chen, Sixian Chen, Jiaxi Wu, Wenyi Peng, Shengyi Yuan, Deqing Li, Gang Li, Aruo Nan","doi":"10.1186/s12943-025-02283-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02283-0","url":null,"abstract":"Lung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression. We identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression. This study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression. o8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment. ROS induce circPLCE1 o8G modification, and AUF1 specifically recognizes o8G modification, thereby decreases circPLCE1 stability. circPLCE1 targets the HSC70 protein, increases its ubiquitination level, inhibits CMA activity, and promotes ATG5-dependent macroautophagy via the CMA pathway, altering the fate of tumour cells and ultimately inhibiting lung cancer progression. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"69 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer","authors":"Kishu Ranjan, Barani Kumar Rajendran, Imad Ud Deen, Adrien Costantini, Miguel Lopez de Rodas, Shruti S. Desai, Frankie Scallo, Nicole Gianino, Soldano Ferrone, Kurt A. Schalper","doi":"10.1186/s12943-025-02276-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02276-z","url":null,"abstract":"Resistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein β-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly understood. Using multiplexed immunofluorescence, we spatially mapped CD8+ effector Tumor-Infiltrating Lymphocytes (TILs) and the APM components TAP1 and TAP2 in 819 baseline/pre-treatment NSCLCs from patients treated with and without PD-1 axis blockers in 4 independent cohorts. The impact of TAP1/2 silencing in lung cancer cells using siRNAs and CRISPR/Cas9 was studied using transcriptomic analysis, phosphoprotein arrays, ATAC-sequencing, measurement of surface HLA-peptide complexes and in vitro tumor-antigen specific T-cell killing. We established autologous co-cultures of tumor and immune cells from primary human NSCLCs to study the functional impact of IL4Rα and/or PD-1 blockade using monoclonal antibodies. A high-throughput drug screen supported the identification of compounds able to increase TAP2 expression in NSCLC cells. We identified cancer cell selective TAP2 protein downregulation in 42.4% of treatment naïve NSCLCs associated with reduced sensitivity to immune checkpoint blockers. TAP1 downregulation occurred in 24.4% of lung tumors without survival impact. Silencing of TAP2 in lung cancer cells altered key intracellular immunomodulatory pathways, limited sensitivity to proinflammatory cytokines, reduced the levels of surface peptide-HLA complexes and protected malignant cells from tumor antigen-specific T-cell killing via SOCS1 upregulation. TAP2 loss in human NSCLCs was associated with reduced TAP2 promoter chromatin accessibility and elevated IL-4 IL-4 expression. Treatment with IL-4 reduced TAP2 levels and the chromatin accessibility of the TAP2 gene promoter in NSCLC cells and reproduced all the functional consequences of TAP2 loss. In intact human NSCLC, IL-4 IL-4 transcripts were detected in intratumoral myeloid cells and IL-4Rα blockade increased human NSCLC cell killing by autologous TILs. Epigenetic modulators and other drugs with known anti-cancer activity increased TAP2 expression and its function in lung cancer cells. Our study reveals previously unrecognized functions of TAP2 beyond antigen presentation and establishes a reversible multi-cellular axis mediating adaptive immune evasion and immunotherapy resistance with clinical potential.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer","authors":"Jiali Dai, Xiyi Lu, Chang Zhang, Tianyu Qu, Wei Li, Jun Su, Renhua Guo, Dandan Yin, Pingping Wu, Liang Han, Erbao Zhang","doi":"10.1186/s12943-025-02285-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02285-y","url":null,"abstract":"Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance. Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model. The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"9 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-leveraged CRISPR/Cas systems: icebreaking in trace cancer-related nucleic acids biosensing","authors":"Weipan Peng, Mengting Shi, Bin Hu, Jingyu Jia, Xinyue Li, Nan Wang, Shuli Man, Shengying Ye, Long Ma","doi":"10.1186/s12943-024-02222-5","DOIUrl":"https://doi.org/10.1186/s12943-024-02222-5","url":null,"abstract":"As promising noninvasive biomarkers, nucleic acids provide great potential to innovate cancer early detection methods and promote subsequent diagnosis to improve the survival rates of patient. Accurate, straightforward and sensitive detection of such nucleic acid-based cancer biomarkers in complex biological samples holds significant clinical importance. However, the low abundance creates huge challenges for their routine detection. As the next-generation diagnostic tool, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) with their high programmability, sensitivity, fidelity, single-base resolution, and precise nucleic acid positioning capabilities are extremely attractive for trace nucleic acid-based cancer biomarkers (NABCBs), permitting rapid, ultra-sensitive and specific detection. More importantly, by combing with nanotechnology, it can solve the long-lasting problems of poor sensitivity, accuracy and simplicity, as well as to achieve integrated miniaturization and portable point-of-care testing (POCT) detection. However, existing literature lacks specific emphasis on this topic. Thus, we intend to propose a timely one for the readers. This review will bridge this gap by providing insights for CRISPR/Cas-based nano-biosensing development and highlighting the current state-of-art, challenges, and prospects. We expect that it can provide better understanding and valuable insights for trace NABCBs detection, thereby facilitating advancements in early cancer screening/detection/diagnostics and win practical applications in the foreseeable future. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteogenomic characterization of molecular and cellular targets for treatment-resistant subtypes in locally advanced cervical cancers","authors":"Do Young Hyeon, Dowoon Nam, Hye-Jin Shin, Juhee Jeong, Eunsoo Jung, Soo Young Cho, Dong Hoon Shin, Ja-Lok Ku, Hye Jung Baek, Chong Woo Yoo, Eun-Kyung Hong, Myong Cheol Lim, Sang-Jin Lee, Young-Ki Bae, Jong Kwang Kim, Jingi Bae, Wonyoung Choi, Su-Jin Kim, Seunghoon Back, Chaewon Kang, Inamul Hasan Madar, Hokeun Kim, Suhwan Kim, Duk Ki Kim, Jihyung Kang, Geon Woo Park, Ki Seok Park, Yourae Shin, Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang-Won Lee, Joo-Young Kim","doi":"10.1186/s12943-025-02256-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02256-3","url":null,"abstract":"We report proteogenomic analysis of locally advanced cervical cancer (LACC). Exome-seq data revealed predominant alterations of keratinization-TP53 regulation and O-glycosylation-TP53 regulation axes in squamous and adeno-LACC, respectively, compared to in early-stage cervical cancer. Integrated clustering of mRNA, protein, and phosphorylation data identified six subtypes (Sub1-6) of LACC among which Sub3, 5, and 6 showed the treatment-resistant nature with poor local recurrence-free survival. Elevated immune and extracellular matrix (ECM) activation mediated by activated stroma (PDGFD and CXCL1high fibroblasts) characterized the immune-hot Sub3 enriched with MUC5AChigh epithelial cells (ECs). Increased epithelial-mesenchymal-transition (EMT) and ECM remodeling characterized the immune-cold squamous Sub5 enriched with PGK1 and CXCL10high ECs. We further demonstrated that CIC mutations could trigger EMT activation by upregulating ETV4, and the elevation of the immune checkpoint PVR and neutrophil-like myeloid-derived suppressive cells (FCN1 and FCGR3Bhigh macrophages) could cause suppression of T-cell activation in Sub5. Increased O-linked glycosylation of mucin characterized adeno-LACC Sub6 enriched with MUC5AChigh ECs. These results provide a battery of somatic mutations, cellular pathways, and cellular players that can be used to predict treatment-resistant LACC subtypes and can serve as potential therapeutic targets for these LACC subtypes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"213 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma","authors":"Dhana Sekhar Reddy Bandi, Ganji Purnachandra Nagaraju, Sujith Sarvesh, Julienne L. Carstens, Jeremy B. Foote, Emily C. Graff, Yu-Hua D Fang, Adam B. Keeton, Xi Chen, Jacob Valiyaveettil, Kristy L. Berry, Sejong Bae, Mehmet Akce, Greg Gorman, Karina J. Yoon, Upender Manne, Michael R. Boyd, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Gary A. Piazza, Bassel F. El-Rayes","doi":"10.1186/s12943-025-02288-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02288-9","url":null,"abstract":"Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models. Murine PDAC cells with KRASG12D mutation (KPC-luc or 2838c3-luc) were orthotopically implanted into the pancreas of C57BL/6J mice, and four PDX PDAC tumors with KRAS mutations were implanted subcutaneously in NSG mice. To assess potential to overcome RAS inhibitor resistance, parental and resistant MIA PaCa-2 PDAC cells (KRASG12C mutation) were implanted subcutaneously. Subcutaneously implanted RASWT BxPC-3 cells were used to assess the selectivity of ADT-1004. ADT-1004 potently blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated RAS and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations and increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models resistant to these KRASG12C inhibitors and MRTX1133 resistant KRASG12D mutant cells. As evidence of selectivity for tumors with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"68 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}