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Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway. 黄芪皂苷IV通过TGFβ和刺猬信号通路抑制EREG/ErbB/ERK,从而逆转了非小细胞肺癌对紫杉醇的耐药性。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1007/s13402-024-00999-7
Wenhao Xiu, Yujia Zhang, Dongfang Tang, Sau Har Lee, Rui Zeng, Tingjie Ye, Hua Li, Yanlin Lu, Changtai Qin, Yuxi Yang, Xiaofeng Yan, Xiaoling Wang, Xudong Hu, Maoquan Chu, Zhumei Sun, Wei Xu

Purpose: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.

Method: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

Results: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.

Conclusions: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

目的:紫杉醇是治疗晚期非小细胞肺癌(NSCLC)的一线化疗药物,但它经常引起获得性耐药性,导致治疗失败。因此,筛选并鉴定可使耐药癌细胞对化疗药物重新敏感的紫杉醇耐药性逆转剂的机制至关重要:方法:采用细胞活力、成球和异种移植试验评估 ASIV 逆转紫杉醇耐药性的能力。免疫组化、细胞因子应用、小干扰RNA、小分子抑制剂和RNA-seq等方法被用于表征ASIV抑制epiregulin(EREG)和下游信号转导以逆转taxol耐药性的分子机制:结果:ASIV通过抑制NSCLC中球形细胞的干性相关基因逆转了紫杉醇耐药。机制探索发现,ASIV促进了EREG的K48连接多泛素化和降解。此外,化疗药物也会触发EREG。因此,EREG与ErbB受体结合并激活ERK信号,从而调控干性相关基因的表达。抑制EREG/ErbB/ERK可抑制干性相关基因,从而逆转对紫杉醇的耐药性。最后,研究人员观察到,TGFβ和刺猬信号是EREG/ErbB/ERK的下游,可以使用抑制剂来逆转NSCLC对紫杉醇的耐药性:这些研究结果表明,ASIV抑制EREG可通过EREG/ErbB/ERK-TGFβ和Hedgehog轴抑制NSCLC的干性,从而逆转紫杉醇耐药性。
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引用次数: 0
Mitochondria in tumor immune surveillance and tumor therapies targeting mitochondria. 肿瘤免疫监视中的线粒体和针对线粒体的肿瘤疗法。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1007/s13402-024-01000-1
Lvyuan Li, Yi Zhang, Qiling Tang, Chunyu Wu, Mei Yang, Yan Hu, Zhaojian Gong, Lei Shi, Can Guo, Zhaoyang Zeng, Pan Chen, Wei Xiong

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

线粒体在细胞能量产生和代谢调节中发挥着核心作用,其功能已被确定为影响肿瘤免疫反应的关键因素。本综述全面概述了在了解线粒体在肿瘤免疫监视中的作用方面取得的最新进展,包括先天性免疫反应和适应性免疫反应。具体来说,它概述了线粒体如何影响肿瘤免疫系统的功能,强调了线粒体在调节免疫细胞行为以促进或抑制肿瘤发生和发展方面的关键作用。此外,这篇综述还重点介绍了针对线粒体的新兴药物干预措施,包括在癌症治疗中具有巨大潜力的新型小分子药物。通过深入分析,本综述探讨了这些创新策略如何改善肿瘤治疗的疗效和前景。
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引用次数: 0
Unveiling therapeutic avenues targeting xCT in head and neck cancer. 揭示针对头颈部癌症 xCT 的治疗途径。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-03 DOI: 10.1007/s13402-024-00997-9
Jaewang Lee, Jong-Lyel Roh

Head and neck cancer (HNC) remains a major global health burden, prompting the need for innovative therapeutic strategies. This review examines the role of the cystine/glutamate antiporter (xCT) in HNC, specifically focusing on how xCT contributes to cancer progression through mechanisms such as redox imbalance, ferroptosis, and treatment resistance. The central questions addressed include how xCT dysregulation affects tumor biology and the potential for targeting xCT to enhance treatment outcomes. We explore recent developments in xCT-targeted current and emerging therapies, including xCT inhibitors and novel treatment modalities, and their role in addressing therapeutic challenges. This review aims to provide a comprehensive analysis of xCT as a therapeutic target and to outline future directions for research and clinical application.

头颈癌(HNC)仍然是全球主要的健康负担,因此需要创新的治疗策略。这篇综述探讨了胱氨酸/谷氨酸拮抗剂(xCT)在HNC中的作用,特别关注xCT如何通过氧化还原失衡、铁变态反应和耐药性等机制促进癌症进展。研究的核心问题包括 xCT 失调如何影响肿瘤生物学以及靶向 xCT 提高治疗效果的潜力。我们探讨了以 xCT 为靶点的现有疗法和新兴疗法的最新进展,包括 xCT 抑制剂和新型治疗模式,以及它们在应对治疗挑战方面的作用。本综述旨在全面分析作为治疗靶点的xCT,并概述未来的研究和临床应用方向。
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引用次数: 0
IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells. IRE1α抑制剂可增强三阴性乳腺癌细胞对紫杉醇的敏感性。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-06-18 DOI: 10.1007/s13402-024-00961-7
Min Wu, Lin Zhang, Lifu Pi, Layang Liu, Siyu Wang, Yujie Wu, Hongli Pan, Mingyao Liu, Zhengfang Yi

Purpose: Breast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low. Paclitaxel is the first-line drug for the treatment of TNBC, which can inhibit cell mitosis. However, many patients develop drug resistance during treatment, leading to chemotherapy failure. Therefore, finding new therapeutic combinations to overcome TNBC drug resistance can provide new strategies for improving the survival rate of TNBC patients.

Methods: Cell viability assay, RT-qPCR, Colony formation assay, Western blot, and Xenogeneic transplantation methods were used to investigate roles and mechanisms of IRE1α/XBP1s pathway in the paclitaxel-resistant TNBC cells, and combined paclitaxel and IRE1α inhibitor in the treatment of TNBC was examined in vitro and in vivo.

Results: We found activation of UPR in paclitaxel-resistant cells, confirming that IRE1α/XBP1 promotes paclitaxel resistance in TNBC. In addition, we demonstrated that the combination of paclitaxel and IRE1α inhibitors can synergistically inhibit the proliferation of TNBC tumors both in vitro and in vivo,suggesting that IRE1α inhibitors combined with paclitaxel may be a new treatment option for TNBC.

Conclusions: In this study, we demonstrated the important role of IRE1α signaling in mediating paclitaxel resistance and identified that combination therapies targeting IRE1α signaling could overcome paclitaxel resistance and enhance chemotherapy efficacy.

目的:乳腺癌是女性最常确诊的癌症,而三阴性乳腺癌(TNBC)约占所有乳腺癌的 15%-20%。TNBC 具有高度侵袭性和恶性。由于缺乏相关的受体标志物,TNBC 的预后较差,五年生存率较低。紫杉醇是治疗 TNBC 的一线药物,可抑制细胞有丝分裂。然而,许多患者在治疗过程中会产生耐药性,导致化疗失败。因此,寻找克服TNBC耐药性的新疗法组合可为提高TNBC患者生存率提供新策略:方法:采用细胞活力检测、RT-qPCR、集落形成检测、Western blot和异种移植等方法研究IRE1α/XBP1s通路在紫杉醇耐药TNBC细胞中的作用和机制,并在体外和体内观察紫杉醇和IRE1α抑制剂联合治疗TNBC的效果:结果:我们发现紫杉醇耐药细胞中的UPR被激活,证实IRE1α/XBP1促进了TNBC对紫杉醇的耐药。此外,我们还证明了紫杉醇与IRE1α抑制剂联合使用可协同抑制TNBC肿瘤在体外和体内的增殖,这表明IRE1α抑制剂与紫杉醇联合使用可能是治疗TNBC的一种新选择:本研究证实了IRE1α信号传导在介导紫杉醇耐药中的重要作用,并发现针对IRE1α信号传导的联合疗法可以克服紫杉醇耐药并提高化疗疗效。
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引用次数: 0
Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients. 局部晚期直肠癌患者血浆衍生小细胞外囊泡的特征和蛋白质组学分析
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s13402-024-00983-1
Haiyan Chen, Yimin Fang, Siqi Dai, Kai Jiang, Li Shen, Jian Zhao, Kanghua Huang, Xiaofeng Zhou, Kefeng Ding

Background: Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT.

Methods: Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC.

Results: A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity.

Conclusions: Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.

背景:新辅助化放疗(noadjuvant chemoradiotherapy,nCRT)是局部晚期直肠癌(local advanced rectal cancer,LARC)的关键治疗方法,但缺乏预测其疗效的可靠生物标志物仍是一项挑战。因此,本研究旨在评估小细胞外囊泡(sEVs)的蛋白质组组成是否能预测LARC患者的nCRT反应,同时深入研究nCRT后sEVs内的蛋白质组变化:方法:从 LARC 患者中获取 nCRT 前和 nCRT 后的血浆样本。利用基于 TIO2 的方法分离血浆中的 sEV,然后进行基于 LC-MS/MS 的蛋白质组学分析。随后,对差异表达蛋白(DEPs)进行了通路富集分析。此外,还生成了 ROC 曲线,以评估 sEV 蛋白在确定 nCRT 反应方面的预测潜力。对公共数据库进行了查询,以确定与 LARC nCRT 反应相关的 sEV 蛋白相关基因:结果:共有16名患者入组。结果:共有 16 名患者入选,其中 8 名患者获得了病理完全反应(良好反应者,GR),其余 8 名患者未获得完全反应(不良反应者,PR)。我们对治疗前血浆衍生的 sEVs 进行了分析,发现 67 个 DEPs 显著上调,9 个 DEPs 显著下调。值得注意的是,PROC(AUC:0.922)、F7(AUC:0.953)和 AZU1(AUC:0.906)显示出较高的 AUC 值和显著差异(P 值 结论):sEV 蛋白的差异表达可区分 GR 和 PR 患者,有望成为 LARC 患者 nCRT 反应和预后的预测标志物。此外,我们的研究结果还强调了 nCRT 后 sEV 蛋白组成的实质性改变。
{"title":"Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients.","authors":"Haiyan Chen, Yimin Fang, Siqi Dai, Kai Jiang, Li Shen, Jian Zhao, Kanghua Huang, Xiaofeng Zhou, Kefeng Ding","doi":"10.1007/s13402-024-00983-1","DOIUrl":"10.1007/s13402-024-00983-1","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT.</p><p><strong>Methods: </strong>Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO<sub>2</sub>-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC.</p><p><strong>Results: </strong>A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity.</p><p><strong>Conclusions: </strong>Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003718","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}
引用次数: 0
Interferon Gamma Inducible Protein 30: from biological functions to potential therapeutic target in cancers. 伽马干扰素诱导蛋白 30:从生物学功能到癌症的潜在治疗靶点。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s13402-024-00979-x
Sen Zhang, Liwen Ren, Wan Li, Yizhi Zhang, Yihui Yang, Hong Yang, Fang Xu, Wanxin Cao, Xiaoxue Li, Xu Zhang, Guanhua Du, Jinhua Wang

Interferon Gamma Inducible Protein 30 (IFI30), also known as Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT), is predominantly found in lysosomes and the cytoplasm. As the sole enzyme identified to catalyze disulfide bond reduction in the endocytic pathway, IFI30 contributes to both major histocompatibility complex (MHC) class I-restricted antigen cross-presentation and MHC class II-restricted antigen processing by decreasing the disulfide bonds of endocytosed proteins. Remarkably, emerging research has revealed that IFI30 is involved in tumorigenesis, tumor development, and the tumor immune response. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of patients. This review provided a comprehensive overview of the research progress on IFI30 in tumor progression, cellular redox status, autophagy, tumor immune response, and drug sensitivity, with a view to providing the theoretical basis for pharmacological intervention of IFI30 in tumor therapy, particularly in immunotherapy.

伽马干扰素诱导蛋白 30(IFI30)又称伽马干扰素诱导溶酶体硫醇还原酶(GILT),主要存在于溶酶体和细胞质中。IFI30 是目前发现的唯一能在内吞途径中催化二硫键还原的酶,它能通过减少内吞蛋白的二硫键,促进主要组织相容性复合体(MHC)Ⅰ类限制的抗原交叉呈递和 MHC Ⅱ类限制的抗原加工。值得注意的是,新的研究发现,IFI30 参与了肿瘤发生、肿瘤发展和肿瘤免疫反应。以 IFI30 为靶点可为癌症治疗提供新策略,并改善患者的预后。本综述全面概述了IFI30在肿瘤进展、细胞氧化还原状态、自噬、肿瘤免疫反应和药物敏感性等方面的研究进展,以期为IFI30在肿瘤治疗尤其是免疫治疗中的药物干预提供理论依据。
{"title":"Interferon Gamma Inducible Protein 30: from biological functions to potential therapeutic target in cancers.","authors":"Sen Zhang, Liwen Ren, Wan Li, Yizhi Zhang, Yihui Yang, Hong Yang, Fang Xu, Wanxin Cao, Xiaoxue Li, Xu Zhang, Guanhua Du, Jinhua Wang","doi":"10.1007/s13402-024-00979-x","DOIUrl":"10.1007/s13402-024-00979-x","url":null,"abstract":"<p><p>Interferon Gamma Inducible Protein 30 (IFI30), also known as Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT), is predominantly found in lysosomes and the cytoplasm. As the sole enzyme identified to catalyze disulfide bond reduction in the endocytic pathway, IFI30 contributes to both major histocompatibility complex (MHC) class I-restricted antigen cross-presentation and MHC class II-restricted antigen processing by decreasing the disulfide bonds of endocytosed proteins. Remarkably, emerging research has revealed that IFI30 is involved in tumorigenesis, tumor development, and the tumor immune response. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of patients. This review provided a comprehensive overview of the research progress on IFI30 in tumor progression, cellular redox status, autophagy, tumor immune response, and drug sensitivity, with a view to providing the theoretical basis for pharmacological intervention of IFI30 in tumor therapy, particularly in immunotherapy.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975152","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}
引用次数: 0
ZNF468-mediated epigenetic upregulation of VEGF-C facilitates lymphangiogenesis and lymphatic metastasis in ESCC via PI3K/Akt and ERK1/2 signaling pathways. ZNF468 介导的 VEGF-C 表观遗传学上调通过 PI3K/Akt 和 ERK1/2 信号通路促进 ESCC 的淋巴管生成和淋巴转移。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s13402-024-00976-0
Jinrong Zhu, Xiangyu Qiu, Xin Jin, Xiaoya Nie, Shengming Ou, Geyan Wu, Jianfei Shen, Rongxin Zhang

Purpose: Dysfunctional lymphangiogenesis is pivotal for various pathological processes including tumor lymph node metastasis which is a crucial cause of therapeutic failure for ESCC. In this study, we aim to elucidate the molecular mechanisms and clinical relevance of Zinc-finger protein ZNF468 in lymphangiogenesis and lymphatic metastasis in ESCC.

Methods: Immunohistochemistry, Western blot, Kaplan-Meier plotter analysis and Gene Set Enrichment Analysis were preformed to detect the association of ZNF468 with lymphangiogenesis and poor prognosis in ESCC patients. Foot-pads lymph node metastasis model, tube formation assay, 3D-culture assay and invasion assay were preformed to verify the effect of ZNF468 on lymphangiogenesis and lymph node metastasis. CUT&Tag analysis, immunoprecipitation and mass spectrometry analysis and ChIP-PCR assay were preformed to study the molecular mechanisms of ZNF468 in lymphangiogenesis.

Results: We found that ectopic expression of ZNF468 was correlated with higher microlymphatic vessel density in ESCC tissues, leading to poorer prognosis of ESCC patients. ZNF468 enhanced the capacity of lymphangiogenesis and promoted lymphatic metastasis in ESCC both in vitro and in vivo. However, silencing ZNF468 reversed these phenotypes in ESCC. Mechanically, we demonstrated that ZNF468 recruits the histone modification factors (PRMT1/HAT1) to increase the levels of H4R2me2a and H3K9ac, which then leads to the recruitment of the transcription initiation complex on the VEGF-C promoter, ultimately promoting the upregulation of VEGF-C transcription. Strikingly, the promoting effect of lymphatic metastasis induced by ZNF468 in ESCC was abrogated by targeting PRMT1 using Arginine methyltransferase inhibitor-1 or silencing VEGF-C. Furthermore, we found that the activation of PI3K/AKT and ERK1/2 signaling is required for ZNF468-medicated lymphatic metastasis in ESCC. Importantly, the clinical relevance between ZNF468 and VEGF-C were confirmed not only in ESCC samples and but also in multiple cancer types.

Conclusion: Our results identified a precise mechanism underlying ZNF468-induced epigenetic upregulation of VEGF-C in facilitating lymphangiogenesis and lymph node metastasis of ESCC, which might provide a novel prognostic biomarker and potential therapeutic for ESCC patients.

目的:淋巴管生成障碍是包括肿瘤淋巴结转移在内的各种病理过程的关键,而淋巴结转移是ESCC治疗失败的重要原因。本研究旨在阐明锌指蛋白 ZNF468 在 ESCC 淋巴管生成和淋巴转移中的分子机制和临床意义:免疫组化、Western blot、Kaplan-Meier plotter分析和基因组富集分析检测ZNF468与ESCC患者淋巴管生成和不良预后的相关性。为了验证 ZNF468 对淋巴管生成和淋巴结转移的影响,研究人员进行了足垫淋巴结转移模型、管形成试验、三维培养试验和侵袭试验。通过CUT&Tag分析、免疫沉淀和质谱分析以及ChIP-PCR检测,研究了ZNF468在淋巴管生成中的分子机制:结果:我们发现ZNF468的异位表达与ESCC组织中淋巴微血管密度的升高相关,从而导致ESCC患者预后较差。ZNF468增强了ESCC的淋巴管生成能力,促进了ESCC在体外和体内的淋巴转移。然而,沉默 ZNF468 可逆转 ESCC 中的这些表型。从机理上讲,我们证明了ZNF468招募组蛋白修饰因子(PRMT1/HAT1)以提高H4R2me2a和H3K9ac的水平,然后导致VEGF-C启动子上的转录起始复合体的招募,最终促进VEGF-C转录的上调。引人注目的是,通过使用精氨酸甲基转移酶抑制剂-1靶向PRMT1或沉默VEGF-C,ZNF468在ESCC中诱导的淋巴转移促进作用被减弱了。此外,我们还发现,ZNF468诱导的ESCC淋巴转移需要PI3K/AKT和ERK1/2信号的激活。重要的是,ZNF468与血管内皮生长因子-C之间的临床相关性不仅在ESCC样本中得到了证实,而且在多种癌症类型中也得到了证实:我们的研究结果确定了 ZNF468 诱导的 VEGF-C 表观遗传学上调促进 ESCC 淋巴管生成和淋巴结转移的精确机制,这可能为 ESCC 患者提供一种新的预后生物标志物和潜在疗法。
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引用次数: 0
A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells. 抗IL10R CAR-T细胞释放抗CD33双特异性抗体的双靶向方法可增强对急性髓性白血病细胞的杀伤效果。
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-07-15 DOI: 10.1007/s13402-024-00971-5
Zhifeng Yan, Runxia Gu, Haotian Ma, Nianci Chen, Ting Zhang, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang

Background: Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy.

Methods: Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts.

Results: We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs.

Conclusions: Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes.

背景:免疫疗法,包括嵌合抗原受体(CAR)T细胞和双特异性抗体(BsAbs),在急性髓性白血病(AML)的治疗中遇到了一些挑战,包括这些疗法的持久性有限、抗原丢失和白血病干细胞(LSCs)对治疗的耐药性。方法:在这里,我们提出了一种新的双靶向方法,利用工程化的抗IL10R CAR-T细胞分泌靶向CD33的双特异性抗体。这一创新策略源于我们之前的研究,该研究建立了IL-10与急性髓性白血病细胞干性之间的联系,旨在提高靶向效率,同时消灭LSCs和急性髓性白血病囊胚:我们首先证明了这种协同方法在消灭表达不同水平靶抗原的急性髓细胞白血病细胞系和原代细胞方面的卓越疗效,即使是在 CD33 或 IL10R 低表达的情况下也是如此。此外,分泌抗 CD33 bsAbs 的 IL10R CAR-T 细胞(CAR.BsAb-T)不仅能增强 IL10R CAR-T 细胞的激活和诱导细胞毒性,还能增强旁观者 T 细胞的激活和诱导细胞毒性,从而更有效地靶向 CD33 阳性的肿瘤细胞。我们的体内实验进一步证明,CAR.BsAb-T 细胞可以有效地重新定向 T 细胞,减少肿瘤负荷,并且没有明显的毒性。此外,通过这种策略将 bsAbs 运送到肿瘤局部,有助于减轻与原型 bsAbs 快速清除相关的药代动力学挑战:总之,单载体靶向 IL10R CAR(随后分泌 CD33 靶向 bsAb)的工程设计解决了 IL10R 和 CD33 异质性表达导致的免疫逃逸问题,代表了旨在改善治疗效果的急性髓细胞性白血病疗法的一个有希望的进展。
{"title":"A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells.","authors":"Zhifeng Yan, Runxia Gu, Haotian Ma, Nianci Chen, Ting Zhang, Yingxi Xu, Shaowei Qiu, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Min Wang, Jianxiang Wang","doi":"10.1007/s13402-024-00971-5","DOIUrl":"10.1007/s13402-024-00971-5","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy.</p><p><strong>Methods: </strong>Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts.</p><p><strong>Results: </strong>We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs.</p><p><strong>Conclusions: </strong>Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615892","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}
引用次数: 0
Optimizing the spatial immune landscape of CD103+CD8+ tissue-resident memory T cells in non-small cell lung cancer by neoadjuvant chemotherapy. 通过新辅助化疗优化非小细胞肺癌 CD103+CD8+ 组织驻留记忆 T 细胞的空间免疫格局
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 10.1007/s13402-024-00980-4
Guanqun Yang, Mengyu Hu, Siqi Cai, Chaozhuo Li, Liying Yang, Miaoqing Zhao, Hongbiao Jing, Ligang Xing, Xiaorong Sun

Background: Neoadjuvant chemotherapy (NAC) combined with immunotherapy is increasingly used in non-small cell lung cancer (NSCLC). Tissue-resident memory T (TRM) cells are the primary subset responding to anti-cancer immunity. However, the immunomodulatory effects of NAC on TRM cells remain unknown.

Methods: We established two NSCLC cohorts including patients undergoing upfront surgery (US) and NAC followed by surgery. Beyond the unpaired comparison between the US cohort (n = 122) and NAC cohort (n = 141) with resection samples, 58 matched pre-NAC biopsy samples were available for paired comparisons. Using multiplex immunofluorescence, we characterized TRM cells (CD103+CD8+) and four heterogeneous TRM subsets, including naive TRM1 (PD-1-Tim-3-), pre-exhausted TRM2 (PD-1+Tim-3-), TRM3 (PD-1-Tim-3+), and terminally exhausted TRM4 (PD-1+Tim-3+). Cell density, cytotoxicity, and two spatial features were defined to evaluate the effect of NAC on TRM subsets.

Results: The cell densities, infiltration scores, and cancer-cell proximity scores of TRM cells, especially TRM1&2 subsets, were significantly increased after NAC and associated with better prognosis of patients. In Contrast, no significant change was observed in the TRM4 subset, which was associated with poor prognosis. Besides, the cytotoxicity of TRM subsets was unaltered after NAC. Compared with patients without major pathologic response (MPRs), patients with MPR had higher densities of TRM1&2 subsets and higher cancer-cell proximity scores of TRM2&3 subsets. Furthermore, increased density of CD31 + cancer microvessels was positively associated with both TRM and Tnon-RM cells after NAC.

Conclusions: NAC may remodel the cell density and spatial distribution of TRM subsets, which is associated with favorable therapeutic effect and prognosis in patients with NSCLC.

背景:非小细胞肺癌(NSCLC)越来越多地采用新辅助化疗(NAC)联合免疫疗法。组织驻留记忆 T(TRM)细胞是对抗癌免疫做出反应的主要亚群。然而,NAC对TRM细胞的免疫调节作用仍然未知:我们建立了两个 NSCLC 队列,包括接受前期手术(US)和接受 NAC 后再手术的患者。除了对US队列(122人)和NAC队列(141人)的切除样本进行非配对比较外,还提供了58份匹配的NAC前活检样本进行配对比较。我们使用多重免疫荧光鉴定了TRM细胞(CD103+CD8+)和四个异质性TRM亚群,包括天真TRM1(PD-1-Tim-3-)、衰竭前TRM2(PD-1+Tim-3-)、TRM3(PD-1-Tim-3+)和终末衰竭TRM4(PD-1+Tim-3+)。界定了细胞密度、细胞毒性和两个空间特征,以评估 NAC 对 TRM 亚群的影响:结果:NAC治疗后,TRM细胞,尤其是TRM1和TRM2亚群的细胞密度、浸润评分和癌细胞接近评分均显著增加,并与患者的预后改善相关。与此相反,TRM4 亚群则无明显变化,与预后不良有关。此外,TRM 亚群的细胞毒性在 NAC 后没有改变。与无重大病理反应的患者相比,重大病理反应患者的TRM1和TRM2亚群密度更高,TRM2和TRM3亚群的癌细胞接近度评分更高。此外,CD31 +癌微血管密度的增加与NAC后的TRM和Tnon-RM细胞均呈正相关:结论:NAC可重塑TRM亚群的细胞密度和空间分布,这与NSCLC患者的良好疗效和预后有关。
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引用次数: 0
Single-cell RNA transcriptomic analyses of tumor microenvironment of ovarian metastasis in gastric cancer. 胃癌卵巢转移肿瘤微环境的单细胞 RNA 转录组分析
IF 6.6 2区 医学 Q1 Medicine Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s13402-024-00974-2
Guoyu Chen, Mingda Zhang, Xiaolin Lin, Qiqi Shi, Chenxin Xu, Bowen Sun, Xiuying Xiao, Haizhong Feng

Purpose: Ovarian metastasis of gastric cancer (GC), commonly referred to as Krukenberg tumors, leads to a poor prognosis. However, the cause of metastasis remains unknown. Here, we present an integrated single-cell RNA sequencing (scRNA-Seq) analysis of the immunological microenvironment of two paired clinical specimens with ovarian metastasis of GC.

Methods: scRNA-Seq was performed to determine the immunological microenvironment in ovarian metastasis of gastric cancer. CellChat was employed to analyze cell-cell communications across different cell types. Functional enrichment analysis was done by enrichKEGG in clusterProfiler. GEPIA2 was used to assess the influence of certain genes and gene signatures on prognosis.

Results: The ovarian metastasis tissues exhibit a heterogenous immunological microenvironment compared to the primary tumors. Exhaustion of T and B cells is observed in the ovarian metastasis tissues. Compared to the paired adjacent non-tumoral and primary tumors, the ratio of endothelial cells and fibroblasts is high in the ovarian metastasis tissues. Compared to primary ovarian cancers, we identify a specific group of tumor-associated fibroblasts with MFAP4 and CAPNS1 expression in the ovarian metastatic tissues of GC. We further define metastasis-related-endothelial and metastasis-related-fibroblast signatures and indicate that patients with these high signature scores have a poor prognosis. In addition, the ovarian metastasis tissue has a lower level of intercellular communications compared to the primary tumor.

Conclusion: Our findings reveal the immunological microenvironment of ovarian metastasis of gastric cancer and will promote the discovery of new therapeutic strategies for ovarian metastasis in gastric cancer.

目的:胃癌(GC)的卵巢转移通常被称为克鲁肯伯格肿瘤,会导致不良预后。然而,转移的原因仍然不明。方法:采用单细胞RNA测序(scRNA-Seq)技术测定胃癌卵巢转移灶的免疫微环境。采用 CellChat 分析不同类型细胞间的细胞-细胞通讯。在 clusterProfiler 中使用 enrichKEGG 进行功能富集分析。GEPIA2 用于评估某些基因和基因特征对预后的影响:结果:与原发肿瘤相比,卵巢转移灶组织表现出异质性免疫微环境。结果:与原发肿瘤相比,卵巢转移灶组织表现出异质性免疫微环境。与相邻的非肿瘤和原发肿瘤相比,卵巢转移灶组织中内皮细胞和成纤维细胞的比例较高。与原发性卵巢癌相比,我们在 GC 的卵巢转移组织中发现了一组具有 MFAP4 和 CAPNS1 表达的特定肿瘤相关成纤维细胞。我们进一步定义了转移相关内皮细胞和转移相关成纤维细胞特征,并指出这些特征得分较高的患者预后较差。此外,与原发肿瘤相比,卵巢转移组织的细胞间通讯水平较低:我们的研究结果揭示了胃癌卵巢转移的免疫学微环境,将促进胃癌卵巢转移新治疗策略的发现。
{"title":"Single-cell RNA transcriptomic analyses of tumor microenvironment of ovarian metastasis in gastric cancer.","authors":"Guoyu Chen, Mingda Zhang, Xiaolin Lin, Qiqi Shi, Chenxin Xu, Bowen Sun, Xiuying Xiao, Haizhong Feng","doi":"10.1007/s13402-024-00974-2","DOIUrl":"10.1007/s13402-024-00974-2","url":null,"abstract":"<p><strong>Purpose: </strong>Ovarian metastasis of gastric cancer (GC), commonly referred to as Krukenberg tumors, leads to a poor prognosis. However, the cause of metastasis remains unknown. Here, we present an integrated single-cell RNA sequencing (scRNA-Seq) analysis of the immunological microenvironment of two paired clinical specimens with ovarian metastasis of GC.</p><p><strong>Methods: </strong>scRNA-Seq was performed to determine the immunological microenvironment in ovarian metastasis of gastric cancer. CellChat was employed to analyze cell-cell communications across different cell types. Functional enrichment analysis was done by enrichKEGG in clusterProfiler. GEPIA2 was used to assess the influence of certain genes and gene signatures on prognosis.</p><p><strong>Results: </strong>The ovarian metastasis tissues exhibit a heterogenous immunological microenvironment compared to the primary tumors. Exhaustion of T and B cells is observed in the ovarian metastasis tissues. Compared to the paired adjacent non-tumoral and primary tumors, the ratio of endothelial cells and fibroblasts is high in the ovarian metastasis tissues. Compared to primary ovarian cancers, we identify a specific group of tumor-associated fibroblasts with MFAP4 and CAPNS1 expression in the ovarian metastatic tissues of GC. We further define metastasis-related-endothelial and metastasis-related-fibroblast signatures and indicate that patients with these high signature scores have a poor prognosis. In addition, the ovarian metastasis tissue has a lower level of intercellular communications compared to the primary tumor.</p><p><strong>Conclusion: </strong>Our findings reveal the immunological microenvironment of ovarian metastasis of gastric cancer and will promote the discovery of new therapeutic strategies for ovarian metastasis in gastric cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003720","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}
引用次数: 0
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Cellular Oncology
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