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Development and validation of a small extracellular vesicle-derived RNA signature for early diagnosis of lung adenocarcinoma and prognosis in advanced stages. 用于肺腺癌早期诊断和晚期预后的细胞外小泡衍生RNA标记的开发和验证。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-03 DOI: 10.1186/s12943-025-02524-2
Rui Meng,Yanjun Gao,Zheng Peng,Hua Chen,Yida Li,Yu Liu,Lanxiao Shen,Huanle Pan,Liangcheng Zheng,Dezhi Cheng,Xiaoming Lin,Wenjie Sun,Congying Xie
This study developed and validated a diagnostic signature comprising five small extracellular vesicle (sEV)-derived long RNAs (ATF4, GRAP2, MCL1, PAK2, PIK3CB) for distinguishing early-stage lung adenocarcinoma (LUAD) from benign pulmonary nodules and assessing prognosis in advanced LUAD. Utilizing a multi-center cohort of 698 participants, researchers employed RNA sequencing and quantitative PCR to analyze plasma sEV RNA profiles. Differentially expressed mRNAs and long intergenic non-coding RNAs (lincRNAs) were identified using LASSO regression to construct a diagnostic model. The signature demonstrated high diagnostic accuracy with an area under the curve (AUC) of 0.971 in the validation cohort and 0.950 in the prospective cohort. It also surpassed low-dose CT sensitivity (95.24% vs. 71.43%), specificity (100% vs. 93.96%), positive predictive value (100% vs. 45.45%) and negative predictive value (99.67% vs. 97.90%) in the prospective cohort. In advanced LUAD patients undergoing chemoradiotherapy or PD-L1 inhibitor therapy, lower expression of these RNAs correlated with improved progression-free survival (PFS; HR = 0.38-0.39). The signature integrates non-invasively detected sEV RNAs to complement LDCT, addressing its high false-positive rate, and offers prognostic insights for personalized treatment strategies. These findings highlight the clinical potential of sEV-derived long RNAs in early LUAD detection and precision oncology.
本研究开发并验证了一种由5种细胞外小泡(sEV)衍生的长rna (ATF4、GRAP2、MCL1、PAK2、PIK3CB)组成的诊断特征,用于区分早期肺腺癌(LUAD)和良性肺结节,并评估晚期LUAD的预后。利用698名参与者的多中心队列,研究人员采用RNA测序和定量PCR分析血浆sEV RNA谱。差异表达mrna和长基因间非编码rna (lincRNAs)通过LASSO回归进行鉴定,构建诊断模型。该特征具有较高的诊断准确性,验证队列的曲线下面积(AUC)为0.971,前瞻性队列的AUC为0.950。在前瞻性队列中,它也超过了低剂量CT的敏感性(95.24%对71.43%)、特异性(100%对93.96%)、阳性预测值(100%对45.45%)和阴性预测值(99.67%对97.90%)。在接受放化疗或PD-L1抑制剂治疗的晚期LUAD患者中,这些rna的低表达与无进展生存期的改善相关(PFS; HR = 0.38-0.39)。该特征集成了非侵入性检测的sEV rna,以补充LDCT,解决其高假阳性率,并为个性化治疗策略提供预后见解。这些发现强调了sev衍生的长rna在早期LUAD检测和精确肿瘤学中的临床潜力。
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引用次数: 0
Gut microbial metabolites in cancer immunomodulation. 肠道微生物代谢物在癌症免疫调节中的作用。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-03 DOI: 10.1186/s12943-025-02521-5
Hengshuo Liu,Xingyu Xiong,Weizhen Zhu,Sheng Wang,Weichao Huang,Guoqing Zhu,Hang Xu,Lu Yang
Gut microbiota-derived metabolites are emerging as systemic "remote immunoregulators" that shape tumor immunity across tissues. Integrating evidence across short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines and other metabolites, we advance a metabolite-immune pathway-cancer framework that links receptor-mediated signaling, epigenetic remodeling and metabolic reprogramming to context-dependent, bidirectional immune effects. Importantly, in addition to the g protein-coupled receptor / aryl hydrocarbon receptor pathway, the selected microbial small molecule metabolites are the true T-cell receptor ligands of unconventional T cells, directly shaping the tissue resident immune and tumor microenvironment, supplementing the receptor signaling and epigenetic programs in our framework. We synthesize how these metabolites recalibrate the tumor immune microenvironment-modulating antigen presentation, T-cell effector fitness and exhaustion, regulatory T-cell activity, and myeloid polarization-and why the same metabolite can either potentiate immune surveillance or entrench immunosuppression depending on ligand-receptor pairing, dose and tissue niche. We compare tumor-type specific patterns (e.g., colorectal, liver, lung, breast and prostate cancers) to highlight common circuits and organ-restricted idiosyncrasies. Methodologically, we outline how single-cell and spatial multi-omics, imaging mass spectrometry and functional biosensors now enable co-registration of metabolite exposure with immune-cell states in human tumors, providing an actionable basis for biomarker discovery. Given ongoing debate about signals attributed to intratumoral microbiota in low-biomass tumor tissues, we foreground quantifiable, spatially mappable and pharmacologically tractable metabolite-receptor pathways, using microbe-associated molecular patterns / translocation as comparators to judge when chemical signals should be prioritized as intervention targets. Finally, we evaluate precision intervention avenues-including fecal microbiota transplantation, rational bacterial consortia, engineered microbes and nanoparticle-enabled metabolite delivery-and propose stratification rules that pair metabolite/receptor signatures with fit-for-purpose delivery. Together, mapping tissue-specific metabolite-immune circuits and embedding them in robust biomarker frameworks may convert microbial metabolites from correlative markers into therapeutic targets and tools, improving the efficacy and durability of cancer immunotherapy.
肠道微生物衍生的代谢物正在成为系统性的“远程免疫调节剂”,影响组织间的肿瘤免疫。整合短链脂肪酸、色氨酸衍生物、次级胆胆酸、多胺和其他代谢物的证据,我们提出了一个代谢物-免疫途径-癌症框架,将受体介导的信号传导、表观遗传重塑和代谢重编程与环境依赖的双向免疫效应联系起来。重要的是,除了g蛋白偶联受体/芳烃受体途径外,所选择的微生物小分子代谢物是非常规T细胞的真正T细胞受体配体,直接塑造组织驻留免疫和肿瘤微环境,补充了我们框架中的受体信号和表观遗传程序。我们综合了这些代谢物如何重新校准肿瘤免疫微环境-调节抗原呈递,t细胞效应适应度和耗竭,调节性t细胞活性和骨髓极化-以及为什么相同的代谢物可以根据配体-受体配对,剂量和组织生态位增强免疫监视或巩固免疫抑制。我们比较肿瘤类型的特定模式(例如,结肠直肠癌,肝癌,肺癌,乳腺癌和前列腺癌),以突出共同的电路和器官限制性特质。在方法学上,我们概述了单细胞和空间多组学、成像质谱和功能性生物传感器如何使人类肿瘤中代谢物暴露与免疫细胞状态的共同登记成为可能,为生物标志物的发现提供了可行的基础。鉴于关于低生物量肿瘤组织中肿瘤内微生物群信号的持续争论,我们展望了可量化的、空间可映射的和药理学上可处理的代谢物受体途径,使用微生物相关的分子模式/易位作为比较物来判断何时应优先考虑化学信号作为干预目标。最后,我们评估了精确的干预途径——包括粪便微生物群移植、合理的细菌联盟、工程微生物和纳米颗粒驱动的代谢物递送——并提出了将代谢物/受体特征与适合目的的递送配对的分层规则。总之,绘制组织特异性代谢物免疫回路并将其嵌入强大的生物标志物框架可能会将微生物代谢物从相关标记物转化为治疗靶点和工具,从而提高癌症免疫治疗的疗效和持久性。
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引用次数: 0
Correction: Harnessing ExDNA for precision Exatecan delivery in cancer: a novel antibody-drug conjugate approach. 更正:利用ExDNA在癌症中精确递送Exatecan:一种新的抗体-药物偶联方法。
IF 33.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-03 DOI: 10.1186/s12943-025-02539-9
Zaira Ianniello, Huimei Lu, Elias Quijano, Daniel A Colón-Ríos, Madison Rackear, Venu Bommireddy, Dale L Ludwig, Zhiyuan Shen, Peter M Glazer
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引用次数: 0
Multi-omic profiling provides insights into the heterogeneity, microenvironmental features, and biomarker landscape of small-cell lung cancer. 多组学分析提供了对小细胞肺癌异质性、微环境特征和生物标志物景观的见解。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-02 DOI: 10.1186/s12943-025-02514-4
Mingchao Xie,Miljenka Vuko,Shashank Saran,Siyu Liu,Andrew G Chambers,Hana Baakza,Helen K Angell,Felicia Ng,Carl M Gay,Robert J Cardnell,Felix J Segerer,Alma Andoni,Jaime Rodriguez-Canales,Paul M Waring,Markus Schick,J Carl Barrett,Lauren A Byers,Giulia Fabbri
BACKGROUNDGreater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.METHODSWe explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.RESULTSMulti-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.CONCLUSIONSThis multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.
背景:需要更好地了解小细胞肺癌(SCLC)的不同治疗敏感性,特别是对免疫治疗的敏感性。方法:通过对来自159例初次治疗患者的肿瘤组织样本进行综合分子表征,利用遗传、表观遗传、转录和蛋白质组学分析,对多种生物学相关标记(包括转录亚型定义蛋白)进行免疫组化染色,并利用多重免疫荧光进行空间免疫分析,探讨SCLC的异质性。结果多组学分析证实了神经内分泌和非神经内分泌亚型之间的高度异质性。甲基组学分析确定了四个甲基组簇,它们可以增强亚型预测、预后和亚型进化的纵向监测。免疫组织化学分析显示,在非神经内分泌亚型中MHC-I的高表达,在化疗中加入免疫治疗具有最大的潜在益处;DLL3高表达与神经内分泌亚型和免疫冷肿瘤微环境相关。多重免疫荧光显示MHC-I与高表达MHC-I的SCLC肿瘤微环境中免疫细胞的空间排列和表型特征相关,为MHC-I作为免疫治疗反应的潜在生物标志物提供了机制基础。结论:该多模式分析为SCLC的生物学复杂性提供了进一步的见解,并突出了不同疾病亚型的潜在治疗脆弱性。
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引用次数: 0
Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects. 癌症中的铁下垂:代谢、机制和治疗前景。
IF 33.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 DOI: 10.1186/s12943-025-02520-6
Yansheng Wu, Hao Li, Kai Yue, Chao Jing, Yuansheng Duan

Ferroptosis is a form of cell death, distinct from apoptosis, necrosis and autophagy. It is a novel programmed cell death (PCD) triggered by iron accumulation and peroxidation associated with intracellular iron metabolism disorders. Since its naming in 2012, ferroptosis has garnered increasing attention for its role in human diseases, particularly in tumor formation, progression and therapy. Numerous studies have demonstrated that ferroptosis plays a crucial role in killing tumor cells, inhibiting tumor proliferation and metastasis and reversing therapy resistance. Consequently, targeted induction of ferroptosis in tumor cells holds promise as a novel antitumor therapeutic strategy.

铁下垂是细胞死亡的一种形式,不同于细胞凋亡、坏死和自噬。它是一种新型的程序性细胞死亡(PCD),由铁积累和过氧化引起,与细胞内铁代谢紊乱有关。自2012年被命名以来,铁下垂症因其在人类疾病中的作用,特别是在肿瘤形成、进展和治疗中的作用而受到越来越多的关注。大量研究表明,铁下垂在杀伤肿瘤细胞、抑制肿瘤增殖转移、逆转治疗耐药等方面起着至关重要的作用。因此,在肿瘤细胞中靶向诱导铁下垂有望成为一种新的抗肿瘤治疗策略。
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引用次数: 0
Correction: Proteogenomic characterization of molecular and cellular targets for treatment‑resistant subtypes in locally advanced cervical cancers. 更正:局部晚期宫颈癌治疗耐药亚型的分子和细胞靶点的蛋白质基因组特征。
IF 33.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-29 DOI: 10.1186/s12943-025-02522-4
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
{"title":"Correction: 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/s12943-025-02522-4","DOIUrl":"10.1186/s12943-025-02522-4","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"301"},"PeriodicalIF":33.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12664262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retraction Note: Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26+ cancer stem cells in colorectal carcinoma. 注:Raf265对结肠癌细胞和结直肠癌CD26+肿瘤干细胞抗肿瘤和抗转移作用的临床前分析。
IF 33.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-29 DOI: 10.1186/s12943-025-02535-z
Ariel Km Chow, Nathan Sm Cheng, Colin Sc Lam, Lui Ng, Sunny Km Wong, Timothy Mh Wan, Johnny Hw Man, Alvin Hk Cheung, Thomas Cc Yau, Jensen Tc Poon, Wai-Lun Law, Roberta Wc Pang
{"title":"Retraction Note: Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26<sup>+</sup> cancer stem cells in colorectal carcinoma.","authors":"Ariel Km Chow, Nathan Sm Cheng, Colin Sc Lam, Lui Ng, Sunny Km Wong, Timothy Mh Wan, Johnny Hw Man, Alvin Hk Cheung, Thomas Cc Yau, Jensen Tc Poon, Wai-Lun Law, Roberta Wc Pang","doi":"10.1186/s12943-025-02535-z","DOIUrl":"10.1186/s12943-025-02535-z","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"302"},"PeriodicalIF":33.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12664263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma. 下调Sod2会增加不典型扁平病变和发育不良,从而导致胰腺导管腺癌的进展。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-28 DOI: 10.1186/s12943-025-02518-0
Alicia K Fleming Martinez,Heike R Döppler,Ryan Argo,Ligia I Bastea,Brandy H Edenfield,Irene Espositio,Peter Storz
{"title":"Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma.","authors":"Alicia K Fleming Martinez,Heike R Döppler,Ryan Argo,Ligia I Bastea,Brandy H Edenfield,Irene Espositio,Peter Storz","doi":"10.1186/s12943-025-02518-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02518-0","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"90 1","pages":"300"},"PeriodicalIF":37.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613345","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}
引用次数: 0
Senescent SPP1+ macrophages remodel the tumor microenvironment and promote the progression of early-stage lung adenocarcinoma featured with mixed ground glass nodule. 衰老的SPP1+巨噬细胞重塑肿瘤微环境,促进以混合磨玻璃结节为特征的早期肺腺癌的进展。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-27 DOI: 10.1186/s12943-025-02497-2
Hong Zheng,Yan-Qi Li,Xiao Lu,Jiao Zhang,Sha-Sha Yu,Xu-Feng Deng,Xiao-Bing Liu,Man-Yuan Li,Yi Cao,Qian Chen,Yuan Qiu,Quan-Xing Liu,Dong Zhou,Ji-Gang Dai
Most persistent ground glass nodules (GGNs) are eventually diagnosed as early-stage lung adenocarcinoma (LUAD). Delving into the molecular underpinnings of malignant transformation of GGNs will aid in the development of preventive and therapeutic strategies to interrupt the occurrence and progression of early-stage LUAD. Macrophages (Macs) are critical in the formation of immunosuppressive tumor microenvironment (TME). However, its role in triggering the advancement of early-stage LUAD with mixed ground glass nodule (mGGN) is yet to be clarified. Utilizing scRNA-seq analysis on normal lung tissues, ground glass regions, and solid regions of mGGNs, complemented by multicolor immunohistochemistry (mIHC) and flow cytometry, we found an increase and peri-tumoral aggregation of immunosuppressive SPP1+ alveolar Macs and monocyte-derived Macs (Mo-Macs), with a particular emphasis on the Mo-Macs. This accumulation at the tumor margin could obstruct the penetration of immune cells into the tumor's core, thereby promoting the malignant transformation of GGNs. SPP1+ Macs not only display a senescent phenotype but also harbor the potential capacity to foster tumor metastasis and angiogenesis. Clinical data from LUAD tissue array and TCGA-LUAD database revealed a positive association between the tumoral SPP1+ Macs percentage and poor prognosis. Furthermore, SPP1+ Macs could reshape the TME into an immunosuppressive state through interactions with other immune cells. In vitro and in vivo assays revealed SPP1 knockout inhibited the immunosuppressive polarization and senescence of Macs, reversed the immunosuppressive status of TME and reduced the growth of LUAD xenograft tumors. Our findings propose an emerging therapeutic strategy aimed at suppressing SPP1+ Macs, which could potentially decelerate or halt the malignant conversion of GGNs to early-stage LUAD.
大多数持续性磨砂玻璃结节(ggn)最终被诊断为早期肺腺癌(LUAD)。深入研究ggn恶性转化的分子基础将有助于制定预防和治疗策略,以中断早期LUAD的发生和发展。巨噬细胞(Macs)是免疫抑制肿瘤微环境(TME)形成的关键。然而,其在早期LUAD伴混合磨砂玻璃结节(mGGN)进展中的作用尚不清楚。利用scRNA-seq分析正常肺组织、mggn的磨玻璃区和实体区,并辅以多色免疫组织化学(mIHC)和流式细胞术,我们发现免疫抑制SPP1+肺泡Macs和单核细胞源性Macs (Mo-Macs)增加和肿瘤周围聚集,特别是Mo-Macs。这种在肿瘤边缘的积聚会阻碍免疫细胞向肿瘤核心的渗透,从而促进ggn的恶性转化。SPP1+ mac不仅表现出衰老表型,而且还具有促进肿瘤转移和血管生成的潜在能力。来自LUAD组织阵列和TCGA-LUAD数据库的临床数据显示,肿瘤SPP1+ Macs百分比与预后不良呈正相关。此外,SPP1+ mac可以通过与其他免疫细胞的相互作用将TME重塑为免疫抑制状态。体外和体内实验显示,敲除SPP1抑制了Macs的免疫抑制极化和衰老,逆转了TME的免疫抑制状态,降低了LUAD异种移植肿瘤的生长。我们的研究结果提出了一种新的治疗策略,旨在抑制SPP1+ Macs,这可能会减缓或阻止ggn向早期LUAD的恶性转化。
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引用次数: 0
Modeling CIC::DUX4 sarcoma reveals oncogene-mediated MHCI-dependent immune evasion. 建模CIC::DUX4肉瘤揭示癌基因介导的mhci依赖性免疫逃避。
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-11-26 DOI: 10.1186/s12943-025-02485-6
Ajay Ram Vachanaram,Erdong Wei,Ana Mitanoska,William Bassett,Michael Kyba,Darko Bosnakovski
CIC::DUX4 sarcoma (CDS) is a highly aggressive malignancy with limited therapeutic options. Here, we present a doxycycline-inducible CIC::DUX4 chimeric mouse model and a cancer line derived from it, imChCDS, that faithfully recapitulates the molecular, histological, and immunological features of human CDS. We demonstrate that CIC::DUX4 expression alone is sufficient to drive tumorigenesis in permissive lineages of soft connective tissues. The imChCDS cell line retains the transcriptional footprint of its mesenchymal cell of origin, develops metastatic tumors in immunocompetent hosts, and exhibits a clear dependency on the P300/CBP transcriptional co-activators. Notably, we identify CIC::DUX4/P300/CBP-mediated suppression of MHC class I (MHCI) as a key mechanism of CDS immune evasion. Genetical inactivation of CIC::DUX4 or pharmacological inhibition of P300/CBP induces cancer cell cycle arrest, restores MHCI expression, and triggers robust anti-tumor immune responses, thereby transforming the immunologically "cold" CDS microenvironment into a "hot" one and driving tumor regression. Together, these models offer a versatile and physiologically relevant platform to investigate CDS pathogenesis, unravel immune evasion mechanisms, and evaluate emerging therapeutic strategies, including those targeting CIC::DUX4/P300/CBP oncogenic axis.
CIC: DUX4肉瘤(CDS)是一种高度侵袭性的恶性肿瘤,治疗选择有限。在这里,我们提出了一个多西环素诱导的CIC::DUX4嵌合小鼠模型和一个从它衍生的癌细胞系,imChCDS,忠实地概括了人类CDS的分子、组织学和免疫学特征。我们证明CIC::DUX4的表达足以在软结缔组织的允许谱系中驱动肿瘤发生。imChCDS细胞系保留了其起源间充质细胞的转录足迹,在免疫能力强的宿主中发展为转移性肿瘤,并表现出对P300/CBP转录共激活因子的明显依赖。值得注意的是,我们发现CIC::DUX4/P300/ cbp介导的MHCI类(MHCI)抑制是CDS免疫逃避的关键机制。CIC::DUX4基因失活或P300/CBP药理抑制诱导癌细胞周期阻滞,恢复MHCI表达,触发强大的抗肿瘤免疫应答,从而将免疫上的“冷”CDS微环境转化为“热”环境,驱动肿瘤消退。总之,这些模型为研究CDS发病机制、揭示免疫逃避机制和评估新兴治疗策略提供了一个通用的生理学相关平台,包括针对CIC::DUX4/P300/CBP致癌轴的治疗策略。
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引用次数: 0
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Molecular Cancer
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