Translational Oncology最新文献

{"title":"Pterostilbene induces pyroptosis in mouse breast cancer cells through the caspase-3/Gasdermin E signaling pathway and reshapes the tumor immune microenvironment","authors":"Xiaoxia Huang ,&nbsp;Wenhui Yang ,&nbsp;Xinyi Hu ,&nbsp;Li Peng ,&nbsp;Jing Dong ,&nbsp;Lin Li","doi":"10.1016/j.tranon.2025.102454","DOIUrl":"10.1016/j.tranon.2025.102454","url":null,"abstract":"<div><div>There is increasing evidence that the intake of specific dietary supplements may reduce the risk of breast cancer. Pterostilbene (PTE), a naturally occurring stilbene compound that is widely found in berries, induced pyroptosis in EMT6 and 4T1 cells in a dose-dependent manner. Additionally, si Gasdermin E (GSDME) and Z-DEVD-FMK (a caspase-3 enzymatic activity inhibitor) significantly inhibited PTE-induced pyroptosis in these cells. These findings suggest that PTE induces pyroptosis in mouse breast cancer cells through the caspase-3/GSDME signaling pathway. Mice with transplanted EMT6 breast tumors were established to investigate the antitumor activity of PTE in vivo. The results showed that PTE prevented and inhibited breast tumor growth in a dose-dependent manner. GO and KEGG annotation analysis showed that lots of differential genes were concentrated in the immune system. To further verify whether PTE inhibits tumors by reshaping the tumor immune microenvironment (TIME), we detected the proportions of Th cells, CTL cells, NK cells, MDSC cells, TAMs, Treg cells and B cells in the mouse peripheral blood, spleen and breast tumors. And PTE was found to up-regulate the proportions of antitumor immune cells and down-regulate the proportions of immunosuppressive cells. In conclusion, PTE inhibited breast tumor growth by introducing breast caner cells pyroptosis, enhancing antitumor immunity and reshaping the TIME. Consequently, this study has significant implications for the development of PTE and PTE-containing functional foods, dietary supplements, immunomodulatory drugs, and breast cancer treatment adjuvants.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102454"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin43 functions as a non-canonical phenotypic stability factor in promoting hybrid Epithelial/Mesenchymal phenotype in glioblastoma cells","authors":"Anushka Mondal ,&nbsp;Sanchari Saha ,&nbsp;Adrish Ghosh ,&nbsp;Justin D Lathia ,&nbsp;Jayasri Das Sarma","doi":"10.1016/j.tranon.2025.102463","DOIUrl":"10.1016/j.tranon.2025.102463","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a highly malignant and aggressive brain tumor with patients typically experiencing a median survival of 15–18 months after diagnosis. Gap junction protein Connexin43 (Cx43) plays a crucial role in GBM by having both tumor-suppressing and tumor-promoting roles. Here, we identify a critical tumor-promoting role of Cx43 in GBM by functioning as a non-canonical phenotypic stability factor and driving partial EMT, which enhances the acquisition of stemness properties in the cells. Using high-grade mouse astrocytoma cell lines, we found that CT2A cells had higher Cx43 gap junction assembly as compared to KR158 cells. The increased Cx43 assembly in CT2A cells activates the NF-κB signaling pathway, promoting a hybrid E/M phenotype and thereby enhancing self-renewal properties. CT2A cells also exhibited collective cell migration, a characteristic feature of hybrid E/M phenotype, stress resistance, and proliferative properties. To verify Cx43′s role in NF-κB pathway activation, DBT and DBT-Erp-29 cells (with higher Cx43 expression) were studied, showing increased NF-κB activation in DBT-Erp-29 cells. Interestingly, KR158 cells formed longer tunneling nanotubes to expedite alternative cellular communication due to reduced gap junctional intercellular communication (GJIC). These results offer valuable insights into targeting Cx43-mediated signaling pathways due to the potential tumor-promoting role of Cx43.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102463"},"PeriodicalIF":5.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning–guided single-cell multiomics uncovers GDF15-driven immunosuppressive niches in NSCLC: A translational framework for overcoming anti-PD-1 resistance","authors":"Xianfei Zhang ,&nbsp;Zhengxin Yin ,&nbsp;Xueyu Chen ,&nbsp;Nengchong Zhang ,&nbsp;Shengjia Yu ,&nbsp;Congcong Zhu ,&nbsp;Lianggang Zhu ,&nbsp;Liulan Shao ,&nbsp;Bin Li ,&nbsp;Runsen Jin ,&nbsp;Hecheng Li","doi":"10.1016/j.tranon.2025.102459","DOIUrl":"10.1016/j.tranon.2025.102459","url":null,"abstract":"<div><div>Immune checkpoint blockade (ICB) has transformed non-small cell lung cancer (NSCLC) treatment, but durable clinical responses remain limited, underscoring the need for robust predictive biomarkers. We integrated multiomics profiling with machine learning to systematically identify determinants of ICB efficacy. Comparative evaluation of 22 survival algorithms across four NSCLC cohorts (n=156) led to the development of an Accelerated Oblique Random Survival Forest model, which outperformed conventional Cox regression and deep learning methods in predictive accuracy (training C-index=0.864; test C-index=0.748). Single-cell RNA sequencing of an immunotherapy-treated cohort revealed that high-risk tumors harbor malignant epithelial subclusters expressing growth differentiation factor 15 (GDF15), a transforming growth factor-β superfamily member implicated in immune evasion. Single-cell non-negative matrix factorization identified GDF15 as a network hub regulating proliferative dominance. External validation using melanoma cohorts (GSE91061) confirmed the pan-cancer predictive relevance of GDF15 and its associated tumor cluster. Functional studies utilizing GDF15-knockdown Lewis lung carcinoma cells showed no significant effect on intrinsic tumor proliferation or growth under immune stress (both p&gt;0.05). GDF15 deletion significantly potentiated PD-1 inhibitor efficacy in vivo, reducing tumor mass by 94.41±6.53 % (SH1) and 94.54±5.21 % (SH2) compared with 3.39±54.90 % in empty vector controls (p&lt;0.01 for all comparisons). CD8⁺ T cell infiltration was also substantially enhanced (81.62±4.79 % [SH1] and 123.50±10.02 % [SH2] vs. 29.63±22.17 % [EV], p&lt;0.05). These findings implicate GDF15 as a regulator of the immunosuppressive tumor microenvironment. Our findings position GDF15 as a first-in-class biomarker for predicting ICB resistance; they establish a translational framework that bridges computational prediction with single-cell mechanistic insights to inform NSCLC immunotherapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102459"},"PeriodicalIF":5.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating mucosa-associated invariant T cells are decreased and have impaired function in patients with diffuse large B-cell lymphoma","authors":"Jingru Liu ,&nbsp;Jiadi Chen ,&nbsp;Shucheng Chen ,&nbsp;Yanrong Huang ,&nbsp;Kaiming Xu ,&nbsp;Danni Cai ,&nbsp;Xinai Liao ,&nbsp;Ruolan You ,&nbsp;Xiaolin Xu ,&nbsp;Xiaoting Wang ,&nbsp;Diyu Hou ,&nbsp;Shuxia Zhang ,&nbsp;Fuwen Yang ,&nbsp;Huifang Huang","doi":"10.1016/j.tranon.2025.102461","DOIUrl":"10.1016/j.tranon.2025.102461","url":null,"abstract":"<div><div>Mucosa-associated invariant T (MAIT) cells are associated with tumor immunity. However, their role in diffuse large B-cell lymphoma (DLBCL) remains unclear. Therefore, this study aimed to elucidate frequency and functional characteristics of circulating MAIT cells in DLBCL patients. The findings revealed a significant reduction in the frequency of circulating MAIT cells in DLBCL patients compared to age-matched healthy controls. Moreover, circulating MAIT cells from DLBCL patients exhibited proapoptotic and senescent phenotypes and demonstrated dysfunction, as evidenced by elevated expression of activation and exhaustion markers, including CD69, CD25, HLA-DR, PD-1, and Tim-3. MAIT cells derived from DLBCL produced lower levels of crucial anti-tumor cytokines, such as interferon-gamma, interleukin-17, tumor necrosis factor-α and granzyme B, suggesting impaired anti-tumor immunity. Additionally, MAIT cells from DLBCL patients showed diminished cytotoxicity against DLBCL cells compared to those from healthy donors. Notably, a lower frequency of circulating MAIT cells in patients with DLBCL was associated with poor prognosis. In summary, this study reveals reduced and impaired circulating MAIT cells in DLBCL patients, suggesting their importance in anti-lymphoma immunity.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102461"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and validation of synergistic drug strategies targeting macrophage polarization in triple-negative breast cancer via single-cell transcriptomics and deep learning","authors":"Qi Qi ,&nbsp;Wenhao Yang ,&nbsp;Liang Li,&nbsp;Yuheng Tang,&nbsp;Yongzhi Chen,&nbsp;Hui Wang,&nbsp;Sun Yingjie,&nbsp;Jialin Shi,&nbsp;Samina Gul,&nbsp;Wenru Tang,&nbsp;Jianyu Pang,&nbsp;Xiaoli Xie","doi":"10.1016/j.tranon.2025.102457","DOIUrl":"10.1016/j.tranon.2025.102457","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) presents therapeutic challenges due to its immunosuppressive tumor microenvironment (TME) and limited targeted options. Analyzing scRNA-seq data from 24 TNBC patients using integrated transcriptomics, machine-learning, and pseudo-time trajectory mapping, we developed a macrophage differentiation-based classifier (MMDCSS) (CD93, CHI3L1, ZBTB20) with remarkable prognostic accuracy (C-index: 0.929, 3-year AUC: 0.907). Computational pharmacology identified finasteride as a ZBTB20 modulator (binding energy:7.7 kcal/mol) capable of reversing tumor-induced M2 macrophage polarization. Finasteride significantly enhanced doxorubicin efficacy ex vivo and in vivo by reprogramming the TME, reducing M2 macrophage infiltration while promoting an M1 phenotype. Mechanistically, finasteride upregulated ZBTB20, counteracting TNBC-mediated suppression of this M1-associated transcription factor. Our findings establish ZBTB20 as a key regulator of macrophage polarization in TNBC and introduce finasteride as a clinically viable agent to reverse TME immunosuppression. Targeting macrophage polarization via ZBTB20 modulation, particularly by repurposing finasteride, offers a promising therapeutic strategy for TNBC with immediate translational potential.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102457"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing ovarian cancer prognosis with an artificial intelligence-derived model: Multi-omics integration and therapeutic implications","authors":"You Wu ,&nbsp;Kunyu Wang ,&nbsp;Yan Song ,&nbsp;Bin Li","doi":"10.1016/j.tranon.2025.102439","DOIUrl":"10.1016/j.tranon.2025.102439","url":null,"abstract":"<div><h3>Background</h3><div>Gynecological malignancies, particularly ovarian cancer, pose a formidable challenge to women's wellbeing, as evidenced by the global incidence and mortality rates, emphasizing the pressing need for advanced diagnostic and treatment modalities. The heterogeneity of ovarian cancer poses challenges for traditional therapeutic approaches, necessitating the exploration of novel, precision medicine techniques.</div></div><div><h3>Methods</h3><div>This study leveraged multi-dataset analysis to construct and validate an Artificial Intelligence-Derived Prognostic Index (AIDPI) for ovarian cancer. Transcriptome data from the TCGA, ICGC, and GEO databases were utilized, encompassing bulk and single-cell RNA sequencing. The AIDPI model was developed and refined using univariate Cox regression analysis and an ensemble of machine learning algorithms. Functional analysis, immunoprofiling, and the role of the MFAP4 gene were investigated to elucidate the biological mechanisms underlying the model.</div></div><div><h3>Results</h3><div>The AIDPI model demonstrated superior accuracy in predicting ovarian cancer prognosis compared to existing models. It correlated with clinical treatment outcomes, including chemotherapy responsiveness, and was integrated into a nomogram for improved prognostic stratification. Functional analysis revealed the influence of AIDPI genes on tumor immune infiltration and cell cycle regulation. Single-cell analysis exposed cell type-specific expression patterns, and the MFAP4 gene was identified as a potential therapeutic target due to its association with patient prognosis and modulation of cellular behavior. In clinical samples of ovarian cancer patients, MFAP4 is highly expressed in metastatic lesions and is associated with poor prognosis. In vitro and in vivo experiments, knockdown of MFAP4 reduces the metastasis of ovarian cancer cells.</div></div><div><h3>Conclusion</h3><div>The AIDPI model offers a highly accurate tool for ovarian cancer prognosis and treatment decision-making, underscored by the integration of multi-omics data and artificial intelligence. The model's performance and biological insights provide a foundation for advancing precision medicine in ovarian cancer. MFAP4′s functionality and the influence of DNA methylation present opportunities for prospective research endeavors and potential therapeutic interventions.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102439"},"PeriodicalIF":5.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-expression of tissue factor, TROP2, and NECTIN4 in primary and matched metastatic cervical cancer lesions","authors":"Marit L. Ulvang ,&nbsp;Oda Fløtre Kvile ,&nbsp;Hege F. Berg ,&nbsp;Kathrine Woie ,&nbsp;Ingfrid S. Haldorsen ,&nbsp;Alessandro D. Santin ,&nbsp;Bjørn I. Bertelsen ,&nbsp;Camilla Krakstad ,&nbsp;Mari Kyllesø Halle","doi":"10.1016/j.tranon.2025.102453","DOIUrl":"10.1016/j.tranon.2025.102453","url":null,"abstract":"<div><h3>Background</h3><div>Early detection of cervical cancer (CC) generally leads to favorable prognosis; however, survival rates drop significantly for late-stage or recurrent disease with limited treatment options. Antibody-drug conjugates (ADCs) show promise across multiple cancers but remain sparsely explored in CC.</div></div><div><h3>Objective</h3><div>This study evaluates ADC target expression in primary and metastatic CC to identify potential ADC responders.</div></div><div><h3>Study Design</h3><div>Membrane expression of tissue factor, TROP2 and NECTIN4 was investigated by immunohistochemistry in 522 primary and 194 metastatic CC lesions. Expression levels were scored according to the ASCO/CAP criteria and correlated with clinicopathological features and follow-up data.</div></div><div><h3>Results</h3><div>Tissue factor, TROP2, and NECTIN4 membranous expression were cancer-cell specific and strong (3+) in 29 %, 37 %, and 4 %, and high (≥2+) in 48 %, 68 %, and 12 % of tumors, respectively. High TF and TROP2 expression were predominantly observed in squamous cell and adenosquamous histologies (p&lt;0.001). Overall, 80 % of primary tumors exhibited high expression of at least one of the ADC targets. High levels of tissue factor and TROP2 were detected in 45 % and 70 % of the metastatic lesions, respectively. The proportion of lesions with high NECTIN4 expression was 12 % in primary tumors and 38 % in recurrent lesions.</div></div><div><h3>Conclusions</h3><div>The ADC targets tissue factor and TROP2 are highly expressed in primary and metastatic CC. The prevalence of high NECTIN4 expression is modest in primary tumors but increases significantly in recurrent disease. These findings support the initiation of clinical trials to evaluate safety and efficacy profiles of ADCs targeting tissue factor, TROP2 and NECTIN4 in CC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102453"},"PeriodicalIF":5.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PHF6 and RUNX1 mutations cooperate to accelerate leukemogenesis","authors":"Yueh-Chwen Hsu ,&nbsp;Chi-Yuan Yao ,&nbsp;Chang-Tsu Yuan ,&nbsp;Chien-Chin Lin ,&nbsp;Hsin-An Hou ,&nbsp;Chein-Jun Kao ,&nbsp;Chia-Lang Hsu ,&nbsp;Wen-Chien Chou ,&nbsp;Hwei-Fang Tien","doi":"10.1016/j.tranon.2025.102449","DOIUrl":"10.1016/j.tranon.2025.102449","url":null,"abstract":"<div><h3>Background</h3><div>RUNX1 is a critical transcription factor in hematopoiesis and its mutations occur in various hematological diseases. PHF6 (plant homeodomain finger gene 6) is regarded as an epigenetic modifier, and its mutations are seen in myeloid and lymphoid leukemia. Previous studies have shown positive association of these two mutations. However, the joint pathological effects of these two genetic alterations remained unexplored.</div></div><div><h3>Methods</h3><div>We sought to investigate the pathological basis of the association between these two mutations. We first analyzed the clinical, genetic, and transcriptomic features of our cohort of patients with acute myeloid leuemia (AML) focusing on these two mutations. We transduced <em>RUNX1</em> mutant into the genetically engineered <em>Phf6</em> knockout (KO) mouse model to generate single- and double-mutated mice for <em>in vivo</em> experiments.</div></div><div><h3>Results</h3><div>In our 1188 adult AML patients, we observed frequent co-occurrence of <em>PHF6</em> and <em>RUNX1</em> mutations, and particularly worse clinical outcomes in these double-mutated patients. Double-mutated bone marrow (BM) cells displayed enriched leukemogenesis-related transcriptomic signatures and significantly higher engraftment capacity. The recipient mice transplanted with double-mutated BM cells developed AML with significantly shortened survival. Furthermore, we discovered that the multipotent progenitors (MPPs) were the main cell subpopulation responsible for double-mutated BM cell-induced leukemia. We noted significant up-regulation of high mobility group AT-hook 2 (<em>Hmga2</em>) in double-mutated MPPs and knock-down of <em>Hmga2</em> abated the self-renewal capacity <em>in vitro</em>..</div></div><div><h3>Conclusions</h3><div>Our findings highlighted the synergistic leukemogenic potential of <em>Phf6</em> and <em>RUNX1</em> mutations <em>in vivo</em>, and provided insights into the molecular mechanisms accounting for this very high-risk disease entity.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102449"},"PeriodicalIF":5.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal profiling of hormone receptor positive, HER2 negative metastatic breast cancer through droplet digital PCR-based circulating tumor DNA fragmentomics","authors":"Lorenzo Foffano ,&nbsp;Alessandra Franzoni ,&nbsp;Elisabetta Molteni ,&nbsp;Fabiola Giudici ,&nbsp;Arianna Dri ,&nbsp;Debora Basile ,&nbsp;Linda Cucciniello ,&nbsp;Silvia Buriolla ,&nbsp;Claudia Noto ,&nbsp;Stefania Russo ,&nbsp;Elena Nascimbeni ,&nbsp;Silvia Bolzonello ,&nbsp;Brenno Pastò ,&nbsp;Serena Della Rossa ,&nbsp;Lorenzo Allegri ,&nbsp;Marta Bonotto ,&nbsp;Alessandro Marco Minisini ,&nbsp;Barbara Belletti ,&nbsp;Giuseppe Damante ,&nbsp;Lorenzo Gerratana ,&nbsp;Fabio Puglisi","doi":"10.1016/j.tranon.2025.102456","DOIUrl":"10.1016/j.tranon.2025.102456","url":null,"abstract":"<div><h3>Background</h3><div>In the context of hormone receptor positive, HER2 negative Metastatic breast cancer (MBC), CDK 4/6 inhibitors (CDK4/6i) combined with endocrine therapy represent the standard first-line treatment, improving Progression-Free Survival (PFS) and Overall Survival (OS). Despite these benefits, resistance to treatment develops, necessitating early risk classification to guide clinical management. This study explores the potential of cell-free DNA (cfDNA) fragmentomics, specifically <em>ACTB</em> fragments, in predicting tumor dynamics and treatment outcomes in luminal MBC, based on the principle that shorter DNA fragments are generally indicative of circulating tumor DNA (ctDNA) from tumor cells, while longer fragments are associated with leukocyte lysis.</div></div><div><h3>Methods</h3><div>In the MAGNETIC.1 study, 141 women with luminal-like MBC were enrolled between January 2018 and January 2023. Blood samples were collected at baseline (BL), and after 3 (T3) and 6 (T6) months of treatment. cfDNA was extracted and analyzed using droplet digital PCR (ddPCR) to quantify <em>ACTB</em> fragments (136 bp, 420 bp, and 2,000 bp). Continuous variables were compared using the Mann–Whitney test and Kruskall Wallis test depending on data distribution and number of groups. Categorical variables were compared using the Chi-square test or Fischer’s exact test whenever appropriate. Differences in survival were tested by log-rank test and uni- and multivariable Cox regression.</div></div><div><h3>Results</h3><div>By categorizing the values of actinic fragments into interquartiles (Q1, Q2, and Q3), <em>ACTB</em>_short Q3 at baseline was significantly associated with negative PR expression (RRR 0.27, <em>P</em> = 0.012) and a higher frequency of liver metastasis (RRR = 3.75, <em>P</em> = 0.009). In terms of clinical outcomes, regarding PFS a significant role was observed for baseline <em>ACTB</em>_short Q3 (HR 1.92, <em>P</em> = 0.041) and <em>ACTB</em>_medium Q3 (HR 0.47, <em>P</em> = 0.043), the latter maintaining significance in multivariable analysis (HR 0.33, 95 %, <em>P</em> = 0.012). For OS, <em>ACTB</em>_short Q3 demonstrated a significant impact in both univariable (HR 3.94, <em>P</em> = 0.003) and multivariable analyses (HR 3.25, <em>P</em> = 0.023).</div></div><div><h3>Conclusions</h3><div>This study demonstrates the feasibility of employing a fragmentomics mutation agnostic approach in luminal MBC. Baseline and longitudinal changes in <em>ACTB</em> fragments were significantly associated with clinical outcomes, suggesting their potential as non-invasive biomarkers for early risk classification and monitoring tumor dynamics.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102456"},"PeriodicalIF":5.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mammary tissue microbiome analysis in PyMT mice reveals Methylobacteria as a commensal organism with potential therapeutic applications","authors":"Alfred A. Chan ,&nbsp;Christine Caron ,&nbsp;Marian Navarrete ,&nbsp;Calvin K. Lee ,&nbsp;Juliana Noguti ,&nbsp;Jack D. Bui ,&nbsp;Delphine J. Lee","doi":"10.1016/j.tranon.2025.102451","DOIUrl":"10.1016/j.tranon.2025.102451","url":null,"abstract":"<div><div>Studies have reported differences in specific bacteria comparing the tissue microbiome in human breast cancer versus normal breast tissue, prompting hypotheses for potential therapies or theragnosis. To test these hypotheses using controlled experiments animal models are needed. Therefore, we investigated the microbiome in the gut and mammary tissue in a mouse model of breast cancer. C57BL/6 mice expressing the polyoma middle T antigen in the mammary gland (PyMT) develop spontaneous multifocal breast tumors. Microbiota in the gut and mammary tissue were studied prior to and after development of mammary gland tumors by amplicon and shotgun DNA sequencing. In parallel, RNA sequencing was performed on tumor and normal tissue to measure differences in gene expression associated with breast cancer. Bacteria identified in these studies were administered to mice to test their effects on cancer progression. Bacterial community composition in the gut of healthy or tumor-bearing mice showed wide fluctuation over time and did not organize into discrete clusters. In tumor versus healthy mammary gland tissue, relative abundances of six bacteria were significantly different: <em>Ralstonia, Methylobacterium, Pelomonas, Staphylococcus</em> and <em>Tepidimonas. Methlyobacterium</em> sequences were significantly higher (PERMANOVA, <em>P</em> = 0.013) in healthy tissue when compared to tumor, leading to a hypothesis that <em>Methylobacterium</em> may promote health. When co-transplanted with breast tumor cells, <em>Methylobacterium</em> reduced growth in immune competent mice. Here we describe the gut and mammary tissue microbial composition of healthy and breast tumor-bearing animals, identifying <em>Methylobacterium sp</em> as a commensal bacteria that might have therapeutic potential to reduce breast cancer progression.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"59 ","pages":"Article 102451"},"PeriodicalIF":5.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}