Molecular Cancer最新文献

{"title":"Advances in cancer immunotherapy: historical perspectives, current developments, and future directions","authors":"Meiyin Zhang, Chaojun Liu, Jing Tu, Min Tang, Milad Ashrafizadeh, Noushin Nabavi, Gautam Sethi, Peiqing Zhao, Shijian Liu","doi":"10.1186/s12943-025-02305-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02305-x","url":null,"abstract":"Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions. • Various aspects of immunotherapy, from its historical evolution to modern strategies and clinical applications, are explored. • Immunotherapeutic approaches, including cancer vaccines and oncolytic virus therapy, are discussed. • The efficacy and mechanisms of immune checkpoint inhibitors and adoptive cell therapies are evaluated. • The complexities of the tumor microenvironment and mechanisms of immune evasion are highlighted. • Advances in cytokines, chemokines, nanotechnology, and combination therapies that enhance immunotherapy effectiveness are outlined. • What are ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"37 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916000","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":"The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer","authors":"Emine Atas, Kerstin Berchtold, Michaela Schlederer, Sophie Prodinger, Felix Sternberg, Perla Pucci, Christopher Steel, Jamie D. Matthews, Emily R. James, Cécile Philippe, Karolína Trachtová, Ali A. Moazzami, Nastasiia Artamonova, Felix Melchior, Torben Redmer, Gerald Timelthaler, Elena E. Pohl, Suzanne D. Turner, Isabel Heidegger, Marcus Krueger, Ulrike Resch, Lukas Kenner","doi":"10.1186/s12943-025-02320-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02320-y","url":null,"abstract":"Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910565","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":"Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities","authors":"Sirui Huang, Jing Zhu, Linglu Yu, Yan Huang, Yue Hu","doi":"10.1186/s12943-025-02336-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02336-4","url":null,"abstract":"A growing body of research suggests a bidirectional interaction between cancer and the nervous system. Neural cells exert their effects on tumors by secreting neurotransmitters and cell adhesion molecules, which interact with specific receptors on tumor cells to modulate their behavior. Conversely, tumor-secreted factors, particularly including inflammatory factors, can alter neural activity and increase neuronal excitability, potentially contributing to neurological manifestations such as epilepsy. The immune system also serves as a crucial intermediary in the indirect communication between cancer and the nervous system. These insights have opened promising avenues for novel therapeutic strategies targeting both tumors and their associated neurological complications. In this review, we have synthesized the key biological mechanisms underlying cancer-nervous system interactions that have emerged over the past decade. We outline the molecular and cellular pathways mediating this cross-talk and explore the clinical implications of targeting the nervous system to suppress tumor growth and metastasis, mitigate neurological complications arising from cancer progression, and modulate the immune response through neural regulation in the context of cancer therapy. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 4 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910567","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":"Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives","authors":"Chen Huang, Jiayi Li, Ruiyan Wu, Yangqian Li, Chenliang Zhang","doi":"10.1186/s12943-025-02344-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02344-4","url":null,"abstract":"Pyroptosis is a distinct form of programmed cell death characterized by the rupture of the cell membrane and robust inflammatory responses. Increasing evidence suggests that pyroptosis significantly affects the tumor microenvironment and antitumor immunity by releasing damage-associated molecular patterns (DAMPs) and pro-inflammatory mediators, thereby establishing it as a pivotal target in cancer immunotherapy. This review thoroughly explores the molecular mechanisms underlying pyroptosis, with a particular focus on inflammasome activation and the gasdermin family of proteins (GSDMs). It examines the role of pyroptotic cell death in reshaping the tumor immune microenvironment (TIME) involving both tumor and immune cells, and discusses recent advancements in targeting pyroptotic pathways through therapeutic strategies such as small molecule modulators, engineered nanocarriers, and combinatory treatments with immune checkpoint inhibitors. We also review recent advances and future directions in targeting pyroptosis to enhance tumor immunotherapy with immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines. This study suggested that targeting pyroptosis offers a promising avenue to amplify antitumor immune responses and surmount resistance to existing immunotherapies, potentially leading to more efficacious cancer treatments.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"52 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901762","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":"Lymph node macrophage-targeted interferon alpha boosts anticancer immune responses by regulating CD169-positive phenotype of macrophages","authors":"Ryo Fukuda, Yukio Fujiwara, Hitoshi Maeda, Cheng Pan, Yuki Minayoshi, Hiromu Yano, Yuki Mizuta, Mei Takano, Rin Yamada, Yoichi Saito, Kenshiro Hirata, Shuhei Imoto, Keishi Yamasaki, Kentaro Oniki, Junji Saruwatari, Masaki Otagiri, Hiroshi Watanabe, Yoshihiro Komohara, Toru Maruyama","doi":"10.1186/s12943-025-02324-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02324-8","url":null,"abstract":"CD169+ macrophages in lymph nodes (LNs) activate cytotoxic T lymphocytes (CTLs), which play a crucial role in anticancer immunity, through antigen presentation and co-stimulation by CD169. Interferon alpha (IFNα) is capable of inducing the CD169+ phenotype of macrophages; however, its clinical applications have been hindered by pharmacokinetic limitations—low LN distribution and an inability to target macrophages. To overcome these issues, this study genetically fused mouse IFNα (mIFNα) with mannosylated mouse serum albumin (Man-MSA), and investigated the antitumor effects of the hybrid protein (Man-MSA-mIFNα) or its add-on effects with programmed death-ligand 1 (PD-L1) blockade. To confirm the possibility of CD169+ macrophage-mediated T cell priming, positional information about individual immune cells in LNs of cancer patients was obtained. Traits of Man-MSA-mIFNα, which was prepared using Pichia pastoris to form the high-mannose structure, were characterized by several physicochemical methods. To evaluate the lymphatic drainage of Man-MSA-mIFNα, radioiodine or Cy5-labeled Man-MSA-mIFNα was subcutaneously administered in mice, and then the radioactivity or fluorescence in LNs was analyzed. CD169-diphtheria toxin (DT) receptor (CD169-DTR) mice in which LN CD169+ macrophages can be depleted by DT injection were used to verify whether the antitumor effect of Man-MSA-mIFNα is dependent on LN CD169+ macrophages. Multiplex tissue imaging predicted close proximity of CD169+ macrophages and T cells and positive correlation between the number of CD169+ macrophages and T cells in neighborhoods in LNs of cancer patients. Physicochemical analyses showed that Man-MSA-mIFNα was formed from the fusion of the intact Man-MSA and mIFNα. Man-MSA-mIFNα efficiently induced the CD169+ phenotype of macrophages by its high LN distribution and macrophage-targeting capability, and significantly exerted antitumor activity through CD8+ T cell activation in the LNs, whereas its antitumor effects were canceled in CD169-DTR mice. Finally, combination therapy with PD-L1 blockade markedly suppressed tumor growth in MB49-bearing mice, which exhibit resistance to PD-L1 blockade monotherapy. The present study successfully designed and developed Man-MSA-mIFNα, which efficiently induces the CD169+ phenotype in LN macrophages, contributing to the antitumor immunity. The findings suggest that our novel strategy targeting CD169⁺ macrophages could be a promising immunotherapy for cancer patients who are unresponsive to immune checkpoint inhibitors. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"7 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901760","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":"Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer","authors":"Harrison J. Boka, Rebekah M. Engel, Christine Georges, Paul J. McMurrick, Helen E. Abud","doi":"10.1186/s12943-025-02327-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02327-5","url":null,"abstract":"Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"96 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897946","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":"Therapy-induced senescence is a transient drug resistance mechanism in breast cancer","authors":"Eszter Bajtai, Csaba Kiss, Éva Bakos, Tamás Langó, Anna Lovrics, Éva Schád, Viktória Tisza, Károly Hegedűs, Péter Fürjes, Zoltán Szabó, Gábor E. Tusnády, Gergely Szakács, Ágnes Tantos, Sándor Spisák, József Tóvári, András Füredi","doi":"10.1186/s12943-025-02310-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02310-0","url":null,"abstract":"Therapy-induced senescence (TIS) is considered a permanent cell cycle arrest following DNA-damaging treatments; however, its irreversibility has recently been challenged. Here, we demonstrate that escape from TIS is universal across breast cancer cells. Moreover, TIS provides a reversible drug resistance mechanism that ensures the survival of the population, and could contribute to relapse. TIS was induced in four different breast cancer cell line with high-dose chemotherapy and cultured until cells escaped TIS. Parental, TIS and repopulating cells were analyzed by bulk and single-cell RNA sequencing and surface proteomics. A genetically engineered mouse model of triple-negative breast cancer was used to prove why current senolytics cannot overcome TIS in tumors. Screening the toxicity of a diverse panel of FDA-approved anticancer drugs revealed that TIS meditates resistance to half of these compounds, despite their distinct mechanism of action. Bulk and single-cell RNA sequencing, along with surface proteome analysis, showed that while parental and repopulating cells are almost identical, TIS cells are significantly different from both, highlighting their transient nature. Furthermore, investigating dozens of known drug resistance mechanisms offered no explanation for this unique drug resistance pattern. Additionally, TIS cells expressed a gene set associated with immune evasion and a potential KRAS-driven escape mechanism from TIS. Our results reveal that TIS, as a transient drug resistance mechanism, could contribute to overcome the immune response and to relapse by reverting to a proliferative stage.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893127","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":"Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma","authors":"Bing Liu, Wei Tao, Xuantong Zhou, Li-Di Xu, Yanrui Luo, Xin Yang, Qingjie Min, Miao Huang, Yuge Zhu, Xinrun Cui, Yaqi Wang, Tongyang Gong, Enli Zhang, Yu S. Huang, Weizhi Chen, Shi Yan, Nan Wu","doi":"10.1186/s12943-025-02333-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02333-7","url":null,"abstract":"Early-stage poorly differentiated lung adenocarcinoma (LUAD) is plagued by a high risk of postoperative recurrence, and its prognostic heterogeneity complicates treatment and surveillance planning. We conducted this integrative multi-omics study to identify those patients with a truly high risk of adverse outcomes. Whole-exome, RNA and whole methylome sequencing were carried out on 101 treatment-naïve early-stage poorly differentiated LUADs. Integrated analyses were conducted to disclose molecular characteristics and explore molecular subtyping. Functional validation of key molecules was carried out through in vitro and in vivo experiments. Recurrent tumors exhibited significantly higher ploidy (p = 0.024), the fraction of the genome altered (FGA, p = 0.042), and aneuploidy (p < 0.05) compared to non-recurrent tumors, as well as a higher frequency of CNVs. Additionally, recurrent tumors showed hypomethylation at both the global level and in CpG island regions. Integrative transcriptomic and methylation analyses identified three molecular subtypes (C1, C2, and C3), with the C1 subtype presenting the worst prognosis (p = 0.024). Although frequently mutated genes showed similar mutation frequencies across the three subtypes, the C1 subtype exhibited the highest tumor mutation burden (TMB), mutant-allele tumor heterogeneity (MATH), aneuploidy, and HLA loss of heterozygosity (HLA-LOH), along with relatively lower immune cell infiltration. Furthermore, GINS1 and CPT1C were found to promote LUAD progression, and their high expression correlated with a poor prognosis. This multi-omics study identified three integrative subtypes with distinct prognostic implications, paving the way for more precise management and postoperative monitoring of early-stage poorly differentiated LUAD.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"11 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893126","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":"Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy","authors":"Yufei Lu, Fu Zhao","doi":"10.1186/s12943-025-02334-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02334-6","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell and plasma cell malignancies, and numerous promising targets against solid tumours are being explored. Despite their initial therapeutic success in hematological cancers, relapse occurs in a significant fraction of patients, highlighting the need for further innovations in advancing CAR T cell therapy. Tumour antigen heterogeneity and acquired tumour resistance leading to antigen escape (antigen loss/downregulation) have emerged as a crucial factor contributing to immune escape and CAR T cell resistance, particularly in the case of solid tumours with only limited success achieved to date. In this review, we discuss mechanisms of tumour relapse in CAR T cell therapy and the promising strategies that are under development to overcome multiple resistance mechanisms, thereby reducing outgrowth of antigen escape variants. Specifically, we emphasize the importance of designing clinical translational strategies to enhance CAR T cell crosstalk with host immune cells, eliciting endogenous antitumour immune responses through antigen/epitope spreading, which offers a genuine solution to the limitations of targeting tumour antigen heterogeneity in solid tumours with monospecific T cell therapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"70 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880351","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":"Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis","authors":"Camille Landragin, Melissa Saichi, Marthe Laisné, Adeline Durand, Pacôme Prompsy, Renaud Leclere, Jérémy Mesple, Kyra Borgman, Amandine Trouchet, Marisa M. Faraldo, Aurélie Chiche, Anne Vincent-Salomon, Hélène Salmon, Céline Vallot","doi":"10.1186/s12943-025-02331-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02331-9","url":null,"abstract":"In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"130 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880355","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}