Molecular Cancer最新文献

{"title":"Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment","authors":"Shujie Liu, Anfeng Jiang, Faqing Tang, Minghao Duan, Bin Li","doi":"10.1186/s12943-025-02323-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02323-9","url":null,"abstract":"Cancer remains a significant global health burden due to its high morbidity and mortality. Oncogene-targeted therapy and immunotherapy have markedly improved the 5-year survival rate in the patients with advanced or metastatic tumors compared to outcomes in the era of chemotherapy/radiation. Nevertheless, the majority of patients remain incurable. Initial therapies eliminate the bulk of tumor cells, yet residual populations termed drug-tolerant persister cells (DTPs) survive, regenerate tumor and even drive distant metastases. Notably, DTPs frequently render tumor cross-resistance, a detrimental phenomenon observed in the patients with suboptimal responses to subsequent therapies. Analogous to species evolution, DTPs emerge as adaptative products at the cellular level, instigated by integrated intracellular stress responses to therapeutic pressures. These cells exhibit profound heterogeneity and adaptability shaped by the intricate feedforward loops among tumor cells, surrounding microenvironments and host ecology, which vary across tumor types and therapeutic regimens. In this review, we revisit the concept of DTPs, with a focus on their generation process upon targeted therapy or immunotherapy. We dissect the critical phenotypes and molecule mechanisms underlying DTPs to therapy from multiple aspects, including intracellular events, intercellular crosstalk and the distant ecologic pre-metastatic niches. We further spotlight therapeutic strategies to target DTP vulnerabilities, including synthetic lethality approaches, adaptive dosing regimens informed by mathematical modeling, and immune-mediated eradication. Additionally, we highlight synergistic interventions such as lifestyle modifications (e.g., exercise, stress reduction) to suppress pro-tumorigenic inflammation. By integrating mechanistic insights with translational perspectives, this work bridges the gap between DTP biology and clinical strategies, aiming for optimal efficacy and preventing relapse.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"133 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130297","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":"LMTK3 regulation of EV biogenesis and cargo sorting promotes tumour growth by reducing monocyte infiltration and driving pro-tumourigenic macrophage polarisation in breast cancer.","authors":"Mark Samuels,Christos Karakostas,Simoni Besta,Andrea Lauer Betrán,Katerina Tsilingiri,Charlotte Turner,Reza Shirazi Nia,Niloufar Poudine,Richard Goodyear,William Jones,Apostolos Klinakis,Georgios Giamas","doi":"10.1186/s12943-025-02346-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02346-2","url":null,"abstract":"BACKGROUNDLemur Tail Kinase 3 (LMTK3) promotes cell proliferation, invasiveness and therapy resistance, and its expression correlates with poor survival in several different malignancies, including breast cancer. Crosstalk through extracellular vesicles (EVs) is an increasingly appreciated mechanism of cell communication within the tumour immune microenvironment, which contributes to different aspects of cancer progression and plays a pivotal role in shaping tumour fate.METHODSNanoparticle tracking analysis and transmission electron microscopy were used to study the effects of LMTK3 on EV size, while single particle interferometry allowed us to examine LMTK3-dependent effects on the subpopulation distribution of EVs. Quantitative mass spectrometry was used to profile LMTK3-dependent proteomics changes in breast cancer-derived EVs. Bioinformatics analysis of clinical data along with in vitro and cell-based assays were implemented to explore the effects of LMTK3-dependent EV protein cargo on the tumour immune microenvironment. To elucidate the mechanism through which LMTK3 impacts endosomal trafficking and regulates EV biogenesis, we used a variety of approaches, including in vitro kinase assays, confocal and electron microscopy, as well as in vivo subcutaneous and orthotopic breast cancer mouse models.RESULTSHere, we report that LMTK3 increases the average size of EVs, modulates immunoregulatory EV proteomic cargo and alters the subpopulation distribution of EVs released by breast cancer cells. Mechanistically, we provide evidence that LMTK3 phosphorylates Rab7, a key regulator of multivesicular body (MVB) trafficking, thereby reducing the fusion of MVBs with lysosomes and subsequent degradation of intralumenal vesicles, resulting in altered EV release. Moreover, LMTK3 causes increased packaging of phosphoserine aminotransferase 1 (PSAT1) in EVs, leading to a paracrine upregulation of phosphoglycerate dehydrogenase (PHGDH) in monocytes when these EVs are taken up. PSAT1 and PHGDH play key roles in the serine biosynthesis pathway, which is closely linked to cancer progression and regulation of monocyte behaviour. LMTK3 EV-induced elevated PHGDH expression in monocytes reduces their infiltration into breast cancer 3D spheroids and in vivo breast cancer mouse models. Furthermore, these infiltrating monocytes preferentially differentiate into pro-tumourigenic M2-like macrophages. Additional breast cancer mouse studies highlight the contribution of LMTK3-dependent EVs in the observed immunosuppressive macrophage phenotype. Finally, in vitro experiments show that pharmacological inhibition of LMTK3 reverses the pro-tumourigenic and immunomodulatory effects mediated by EVs derived from LMTK3 overexpressing cells.CONCLUSIONOverall, this study advances our knowledge on the mechanisms of EV biogenesis and highlights a novel oncogenic role of LMTK3 in the breast TME, further supporting it as a target for cancer therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"130 1","pages":"149"},"PeriodicalIF":37.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122049","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":"Biofilm formation by the host microbiota: a protective shield against immunity and its implication in cancer","authors":"Elena Montanari, Giancarla Bernardo, Valentino Le Noci, Martina Anselmi, Serenella M. Pupa, Elda Tagliabue, Michele Sommariva, Lucia Sfondrini","doi":"10.1186/s12943-025-02348-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02348-0","url":null,"abstract":"Human-resident microbes typically cluster into biofilms - structurally organized communities embedded within a matrix of self-produced extracellular polymeric substance (EPS) that serves as a protective shield. These biofilms enhance microbial survival and functional adaptability, favoring a symbiotic relationship with the host under physiological conditions. However, biofilms exhibit a dual role in modulating the immune response. If their ability to promote tolerance is key to safeguarding homeostasis, by contrast, their persistence can overcome the cutting-edge balance resulting in immune evasion, chronic inflammation and development of numerous diseases such as cancer. Recent evidence highlights the significance of cancer-associated microbiota in shaping the tumor microenvironment (TME). These microbial inhabitants often exhibit biofilm-like structures, which may protect them from host immune responses and therapeutic interventions. The presence of biofilm-forming microbiota within the TME may promote chronic inflammation, and release of bioactive molecules that interfere with immune surveillance mechanisms, thereby enabling cancer cells to evade immune destruction. This review delves into the complex interplay between biofilms and cancer, with particular focus on the tumor-associated microbiota and the implications of biofilm involvement in modulating the immune landscape of the TME. Addressing this intricate relationship holds promises for innovative therapeutic approaches aimed at reprogramming the microbiota-cancer axis for better clinical outcomes. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"32 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104580","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":"Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications","authors":"Trang Thao Quoc Pham, Yung-Che Kuo, Wei-Ling Chang, Hao-Jui Weng, Yen-Hua Huang","doi":"10.1186/s12943-025-02289-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02289-8","url":null,"abstract":"The niche microenvironment plays a crucial role in regulating the fate of normal skin stem cells (SSCs) and cancer stem cells (CSCs). Therapeutically targeting the CSC niche holds promise as an effective strategy; however, the dual effects of shared SSC niche signaling in CSCs have contributed to the aggressive characteristics of tumors and poor survival rates in skin cancer patients. The lack of a clear underlying mechanism has significantly hindered drug development for effective treatment. This article explores recent advances in understanding how niche factors regulate cell fate determination between skin stem cells and skin CSCs, along with their clinical implications. The dual roles of key components of the adhesive niche, including the dermo-epidermal junction and adherens junction, various cell types—especially immune cells and fibroblasts—as well as major signaling pathways such as Sonic hedgehog (Shh), Wingless-related integration site (Wnt)/β-catenin, YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), and Notch, are highlighted. Additionally, recent advances in clinical trials and drug development targeting these pathways are discussed. Overall, this review provides valuable insights into the complex interactions between skin cancer stem cells and their microenvironment, laying the groundwork for future research and clinical strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"38 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104539","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: CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1‑529aa protein and regulating PRDX2 protein stability","authors":"Yu Zhang, Jiajia Jiang, Jiayin Zhang, Han Shen, Maoye Wang, Zhen Guo, Xueyan Zang, Hui Shi, Jiayan Gao, Hui Cai, Xinjian Fang, Hui Qian, Wenrong Xu, Xu Zhang","doi":"10.1186/s12943-025-02356-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02356-0","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Mol Cancer 20, 101 (2021)</b></p><p><b>https://doi.org/10.1186/s12943-021-01390-y</b></p><br/><p>Following the publication of the original article [1], the authors have identified two layout-related errors that occurred during the figure assembly or production process. In Figure 2d, the images for the MGC-803 cell invasion assay were inadvertently misplaced. In Additional file 1: Supplementary Figure 1e, the MGC-803 cell invasion assay images were also affected by a similar layout error. The incorrect and correct figure is provided below. The Supplementary Figure 1 has been updated in the Supplementary Information section of this correction note article.</p><p>Incorrect Figure 2:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02356-0/MediaObjects/12943_2025_2356_Figa_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"830\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02356-0/MediaObjects/12943_2025_2356_Figa_HTML.png\" width=\"685\"/></picture></figure><p>Correct Figure 2:</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02356-0/MediaObjects/12943_2025_2356_Figb_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure b\" aria-describedby=\"Figb\" height=\"783\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02356-0/MediaObjects/12943_2025_2356_Figb_HTML.png\" width=\"685\"/></picture></figure><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Zhang Y, Jiang J, Zhang J, et al. CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability. Mol Cancer. 2021;20:101. https://doi.org/10.1186/s12943-021-01390-y.</p><p>Article 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><span>Author notes</span><ol><li><p>Yu Zhang and Jiajia Jiang contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Aoyang Cancer Institute, Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang, 215600, Jiangsu, China</p><p>Yu Zhang, Jiajia Jiang, Jiayin Zhang, Maoye Wang, Zhen Guo, Xueyan Zang, Hui Shi, Jiayan Gao, Hui Qian, Wenrong Xu & Xu Zhang</p></li><li><p>Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China</p><p>Yu Zhang, Jiajia Jiang, Jiayin Zhang, Han Shen, Maoye Wang, Zhen Guo, Xueyan Zang, Hui Shi, Hui Qian, Wenrong Xu & Xu Zhang</p></li><li><p>Department of Laboratory Medicine, Nanjing Drum Tower Hospital, ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"22 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104540","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":"SLAMF receptors: key regulators of tumor progression and emerging targets for cancer immunotherapy","authors":"Jia Li, Tao Fan, Di Wang, Chu Xiao, Ziqin Deng, Wenpeng Cai, Yu Ji, Chunxiang Li, Jie He","doi":"10.1186/s12943-025-02308-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02308-8","url":null,"abstract":"The signaling lymphocytic activation molecule family (SLAMF) consists of nine distinct cell surface receptors predominantly expressed on immune cells, each characterized by unique structural features, expression patterns, downstream signaling pathways, and biological functions. These receptors play critical roles in modulating various immune cell activities within the tumor microenvironment, thereby shaping immune responses in cancer. Although accumulating evidence demonstrates their value as therapeutic targets for developing cancer immunotherapies, the full spectrum of SLAMF receptors in cancer remains incompletely understood. This review aims to provide a comprehensive overview of the molecular characteristics and immunomodulatory functions of each SLAMF receptor, underscoring their pivotal contributions to cancer progression. Furthermore, we also highlight their potential as promising targets for advancing cancer immunotherapeutic strategies. Finally, we discuss clinical trials evaluating the efficacy and safety of SLAMF receptor-based immunotherapies, emphasizing their translational relevance in the development of cancer treatments.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"16 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066791","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":"Perioperative nivolumab and chemotherapy in locally advanced squamous cell carcinoma of the oesophagus: a randomized multicentre phase 2 study with circulating tumor DNA dynamics monitoring","authors":"Heng Jiao, Siyun Lin, Jianmin Gu, Dongxian Jiang, Peng Cui, Zhiliang Huang, Yong Fang, Hao Wang, Miao Lin, Han Tang, Tian Jiang, Guangyi Lin, Shaoyuan Zhang, Hao Yin, Fei Liang, Jingshu Wang, Xuning Fan, Fujun Qiu, Yang Yang, Zhigang Li, Bin Li, Jiaqing Xiang, Xuefeng Leng, Yongtao Han, Chengcheng Li, Luoyan Ai, Yingyong Hou, Guoqiang Wang, Zhihong Zhang, Shangli Cai, Tianshu Liu, Jun Yin, Lijie Tan","doi":"10.1186/s12943-025-02332-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02332-8","url":null,"abstract":"Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status. In this trial, participants recruited from five centers were randomly assigned in a 2:1 ratio to receive either perioperative Nivolumab or a placebo in addition to chemotherapy (cisplatin and paclitaxel), followed by minimally invasive esophagectomy. For those who did not achieve a pathological complete response (pCR), adjuvant treatment with Nivolumab was administered. The main measure of success was the pCR rate, with secondary endpoints including the R0 resection rate, event-free survival, and overall survival. All outcomes and safety measures were assessed based on the intention-to-treat population. ctDNA levels were monitored as exploratory endpoints. Ninety patients were enrolled and randomized to Nivolumab or placebo plus chemotherapy. The pCR rate was slightly higher in the Nivolumab group (15%) compared to the control group (13.3%) (relative risk, 1.13; 95% CI, 0.38 to 3.36). No significant differences were observed in R0 resection rates (96.4% vs. 96.6%; P > 0.05). The median follow-up duration was 24.9 months (interquartile range: 22.8 to 26.7 months). Two-year event-free survival rates were 63.11% in the Nivolumab group versus 60.47% in the chemo group (hazard ratio, 0.97; 95% CI, 0.49 to 1.92). Two-year overall survival rates were 83.32% and 79.4%, respectively (hazard ratio, 0.82; 95% CI, 0.29 to 2.31). All participants were ctDNA positive at baseline, but post-treatment, 89% of the Nivolumab group and 62.5% of the placebo group turned ctDNA negative (P = 0.01). Those negative for ctDNA at all testing points showed significantly better disease-free survival (P < 0.001). Perioperative Nivolumab plus chemotherapy is a viable and safe option for systemically treating locally advanced resectable OSCC. Monitoring minimal residual disease through ctDNA could be potentially valuable for assessing the effectiveness of adjuvant therapy and for prognostic evaluation in a systemic manner. ClinicalTrials.gov registration NCT05213312.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"28 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979439","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":"Dissecting small cell carcinoma of the esophagus ecosystem by single-cell transcriptomic analysis","authors":"Hao-Xiang Wu, Yu-Kun Chen, Ying-Nan Wang, Jia-Ying Chen, Shu-Jing Xiang, Ying Jin, Zi-Xian Wang, Chun-Yu Huang, Lu-Ping Yang, Ye He, Wen-Long Guan, Long Bai, Yan-Xing Chen, Min Wang, Chao-Ye Wang, Run-Jie Huang, Yue Huang, Jin-Ling Zhang, Zhi-Da Lv, Si-Qi Yang, Rui-Hua Xu, Qi Zhao, Feng Wang","doi":"10.1186/s12943-025-02335-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02335-5","url":null,"abstract":"Small cell carcinoma of the esophagus (SCCE) is an aggressive and rare neuroendocrine malignancy with poor prognosis. Here, we firstly performed single-cell transcriptional profiling derived from 10 SCCE patients, with normal esophageal mucosa, adjacent non-malignant tissue and tumors from esophageal squamous cell carcinoma (ESCC) as reference. We observed enrichment of activated regulatory T cells and an angiogenesis-induced niche existed in SCCE compared with ESCC, revealing an immune suppressive and vessel-induced tumor microenvironment (TME) in SCCE. Totally, we identified five TME ecotypes (EC1 ~ 5). Notably, EC1 was highly enriched in SCCE, associating with molecular subtyping and survival outcomes. To dissecting heterogeneity of epithelium in SCCE, we constructed eight transcriptional metaprograms (MPs) that underscored significant heterogeneity of SCCE. High expression of MP5 was linked to neuroendocrine phenotype and poor clinical survival. Collectively, these results, for the first time, systematically deciphered the TME and epithelial heterogeneity of SCCE and provided evidences that SCCE patients might benefit from anti-angiogenesis therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"29 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979403","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":"Death-ision: the link between cellular resilience and cancer resistance to treatments","authors":"Gustavo Baldassarre, Ivana L. de la Serna, François M. Vallette","doi":"10.1186/s12943-025-02339-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02339-1","url":null,"abstract":"One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"4 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979404","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":"Profiling triple-negative breast cancer-specific super-enhancers identifies high-risk mesenchymal development subtype and BETi-Targetable vulnerabilities","authors":"Qing-shan Chen, Rui-zhao Cai, Yan Wang, Ge-hao Liang, Kai-ming Zhang, Xiao-Yu Yang, Dong Yang, De-Chang Zhao, Xiao-Feng Zhu, Rong Deng, Jun Tang","doi":"10.1186/s12943-025-02342-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02342-6","url":null,"abstract":"Super-enhancers (SEs) are critical regulators of tumorigenesis and represent promising targets for bromodomain and extra-terminal domain inhibitors (BETi). However, clinical studies across various solid tumors, including triple-negative breast cancer (TNBC), have demonstrated limited BETi efficacy. This study aims to investigate SE heterogeneity in TNBC and its influence on BETi effectiveness, with the goal of advancing BETi precision treatment strategies and enhancing therapeutic efficacy. We conducted a comprehensive analysis of H3K27ac ChIP-Seq data from TNBC cell lines and clinical samples, integrating multiple bulk RNA-Seq, scRNA-Seq, and stRNA-Seq datasets to characterize the SE landscape and heterogeneity in TNBC. Utilizing various bioinformatics algorithms, CERES scoring, and clinical prognostic data on transcription factors (TFs), we identified core transcriptional regulatory circuits (CRCs) composed of TNBC-specific SEs and master regulators, characterizing different TNBC subtypes. The biological significance of CRCs in these different TNBC subtypes and their influence on BETi sensitivity were evaluated using in vitro and in vivo models. Our findings revealed a distinct SE landscape in TNBC compared to non-TNBC and normal breast epithelium, allowing TNBC to be classified into distinct subtypes based on TNBC-specific SEs. Importantly, we identified a high-risk mesenchymal development subtype, validated across cell lines and transcriptomic analyses, primarily driven by a CRC consisting of the master regulator VAX2 and a TNBC-specific SE. This SE-VAX2 CRC is essential for sustaining the malignant traits of this subtype and increasing its sensitivity to BETi. Our research clarifies the heterogeneity of SEs in TNBC and identifies a high-risk mesenchymal development subtype driven by the SE-VAX2 CRC. The subtype shows more sensitivity to BETi, supporting its precision application in TNBC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"26 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939766","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}