Cancer letters最新文献_第3页

SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling SMARCA4和SMARCA2共同缺陷：一种不常见的分子特征，可定义与染色质重塑缺陷有关的罕见、侵袭性和未分化恶性肿瘤亚群。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-10-04 DOI: 10.1016/j.canlet.2024.217282

Genetic mutations and epigenetic modifications affecting multiple cancer-related genes occur synergistically to drive tumorigenesis. Across a wide spectrum of cancers, pathogenic changes have been identified in members of the SWItch/Sucrose Non-Fermentable complex including its two catalytic subunits, SMARCA4 and SMARCA2. During cancer development, it is not uncommon to lose the function of either SMARCA4 or SMARCA2, however, loss of both together has been reported to be synthetic lethal and therefore unexpected. Co-deficiency of SMARCA4 and SMARCA2 occurs as a pathognomonic feature of the early-onset ovarian cancer Small-cell carcinoma of the ovary, hypercalcemic type. The loss of both catalytic subunits is also described in other rare undifferentiated neoplasms including Thoracic SMARCA4-deficient undifferentiated tumors, Malignant rhabdoid tumors and dedifferentiated or undifferentiated carcinomas, predominantly of lung, gastrointestinal, and endometrial origin. This review provides the first extensive characterization of cancers with concurrent SMARCA4 and SMARCA2 loss through the discussion of shared clinical and molecular features. Further, we discuss the mechanisms triggering the loss of catalytic activity, the cellular processes that are dysfunctional as a consequence, and finally, current therapeutic candidates which may selectively target these cancers.

影响多个癌症相关基因的基因突变和表观遗传修饰会协同驱动肿瘤发生。在多种癌症中，SWItch/蔗糖不发酵复合体成员（包括其两个催化亚基 SMARCA4 和 SMARCA2）的致病性变化已被确定。在癌症发展过程中，SMARCA4 或 SMARCA2 功能丧失的情况并不少见，但据报道，同时丧失这两种功能会导致合成性死亡，因此是意想不到的。SMARCA4和SMARCA2同时缺失是早发卵巢癌卵巢小细胞癌（高钙血症型）的病理特征。在其他罕见的未分化肿瘤中也发现了两种催化亚基的缺失，包括胸腔 SMARCA4 缺失型未分化肿瘤、恶性横纹肌瘤以及主要源于肺、胃肠道和子宫内膜的去分化或未分化癌。本综述通过讨论共同的临床和分子特征，首次对同时存在 SMARCA4 和 SMARCA2 缺失的癌症进行了广泛的描述。此外，我们还讨论了引发催化活性丧失的机制、因此而功能失调的细胞过程，最后还讨论了目前可能选择性地针对这些癌症的候选疗法。

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引用次数: 0

Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer 表观遗传学动力学探索揭示了调节胰腺癌吉西他滨耐药性的超级增殖因子介导的 NDRG1-β-Catenin 轴。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-10-02 DOI: 10.1016/j.canlet.2024.217284

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.

化疗耐药性仍然是胰腺导管腺癌（PDAC）治疗过程中的一个巨大挑战，因此有必要对其潜在的分子机制进行全面探索。这项研究旨在探讨吉西他滨耐药性在 PDAC 发展过程中的动态表观遗传格局，特别关注超级增强子及其调控效应。我们采用成熟的吉西他滨耐药（Gem-R）PDAC细胞系，对表观基因组、增强子连接组和转录组进行了高通量分析。我们的研究结果表明，在吉西他滨敏感型 PDAC 细胞向耐药型 PDAC 细胞过渡的过程中，表观遗传景观和基因组结构发生了显著变化。值得注意的是，我们观察到超级增强子的激活状态有很大的可塑性，在化疗耐药细胞中，这些顺式元件有相当大的比例失活。此外，我们还发现，在功能缺失的超级增强子中，NDRG1超级增强子（NDRG1-SE）是吉西他滨耐药性的关键调节因子。NDRG1-SE失活会诱导WNT/β-catenin信号的激活，从而产生吉西他滨耐药性。这项研究强调了NDRG1超级增强子失活驱动的β-catenin通路激活是获得吉西他滨耐药性的关键调节因子。这些发现增进了我们对 PDAC 生物学的了解，并为开发针对这种恶性疾病化疗耐药性的有效治疗方法提供了宝贵的见解。

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引用次数: 0

Unraveling the NLRP family: Structure, function, activation, critical influence on tumor progression, and potential as targets for cancer therapy 揭开 NLRP 家族的神秘面纱：结构、功能、激活、对肿瘤进展的关键影响以及作为癌症治疗靶点的潜力。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-10-02 DOI: 10.1016/j.canlet.2024.217283

The innate immune system serves as the body's initial defense, swiftly detecting danger via pattern recognition receptors (PRRs). Among these, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing proteins (NLRPs) are pivotal in recognizing pathogen-associated and damage-associated molecular patterns, thereby triggering immune responses. NLRPs, the most extensively studied subset within the NLR family, form inflammasomes that regulate inflammation, essential for innate immunity activation. Recent research highlights NLRPs' significant impact on various human diseases, including cancer. With differential expression across organs, NLRPs influence cancer progression by modulating immune reactions, cell fate, and proliferation. Their clinical significance in cancer makes them promising therapeutic targets. This review provides a comprehensive overview of the structure, function, activation mechanism of the NLRPs family and its potential role in cancer progression. In addition, we particularly focused on the concept of NLRP as a therapeutic target and its potential value in combination with immune checkpoint inhibitors.

先天性免疫系统是人体的第一道防线，通过模式识别受体（PRR）迅速检测危险。其中，核苷酸结合寡聚化结构域样受体家族含吡林结构域蛋白（NLRPs）在识别病原体相关和损伤相关分子模式，从而触发免疫反应方面起着关键作用。NLRPs 是 NLR 家族中研究最为广泛的亚群，它们形成的炎性体可以调节炎症，对先天性免疫的激活至关重要。最新研究强调了 NLRP 对包括癌症在内的各种人类疾病的重大影响。NLRPs 在不同器官的表达各不相同，它们通过调节免疫反应、细胞命运和增殖来影响癌症的进展。NLRPs在癌症中的临床意义使其成为有前景的治疗靶点。本综述全面概述了 NLRPs 家族的结构、功能、激活机制及其在癌症进展中的潜在作用。此外，我们还特别关注了 NLRP 作为治疗靶点的概念及其与免疫检查点抑制剂联用的潜在价值。

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引用次数: 0

Significance of longitudinal Epstein–Barr virus DNA combined with multipoint tumor response for dynamic risk stratification and treatment adaptation in nasopharyngeal carcinoma 纵向 Epstein-Barr 病毒 DNA 与多点肿瘤反应相结合，对鼻咽癌的动态风险分层和治疗适应性具有重要意义。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-29 DOI: 10.1016/j.canlet.2024.217276

Dynamic therapy response is strongly associated with cancer outcomes. This study aimed to evaluate the significance of longitudinal Epstein–Barr virus (EBV) DNA and radiological tumor regression in risk stratification and response-adaptive treatment in locally-advanced nasopharyngeal carcinoma (LA-NPC). In total, 1312 patients from two centers were assigned to the training and validation cohorts. Based on the multipoint examination of EBV-DNA and tumor response, four post-induction chemotherapy, four mid-radiotherapy, and four post-radiotherapy subgroups were established. Then seven phenotypes were further generated according to different permutations and combinations. These phenotypes were subsequently congregated into four response clusters, which reflect distinct biological treatment responses. The four response clusters correlated with an evident 5-year progression-free survival in both the training and external validation cohorts (5-year: training cohort 91.1 %, 82.8 %, 30.6 %, and 10.0 %; external validation 94.4 %, 55.6 %, 40.0 %, and 12.7 %) had superior prognostic performance compared to TNM staging and nomogram model (concordance index: training cohort—0.825 vs. 0.603 vs. 0.756 and external validation—0.834 vs. 0.606 vs. 0.789). Importantly, the response clusters exhibited an excellent capability in selecting candidates who can benefit from adjuvant chemotherapy. In conclusion, risk stratification based on the dynamic assessment of both radiological and biological responses can significantly enhance prognostic insights and shed light on individualized treatment modifications in LA-NPCs.

动态治疗反应与癌症预后密切相关。本研究旨在评估纵向爱泼斯坦-巴氏病毒（EBV）DNA和放射学肿瘤消退在局部晚期鼻咽癌（LA-NPC）风险分层和反应适应性治疗中的意义。共有来自两个中心的1312名患者被分配到训练组和验证组。根据对 EBV DNA 和肿瘤反应的多点检测，建立了四个诱导化疗后、四个放疗中期和四个放疗后亚组。然后根据不同的排列和组合进一步产生了七个表型。这些表型随后被归纳为四个反应集群，它们反映了不同的生物治疗反应。在训练队列和外部验证队列中，这四个反应群与明显的 5 年无进展生存期相关（5 年：训练队列 91.1%、82.8%、30.6% 和 10.0%；外部验证 94.4%、55.6%、40.0% 和 12.7%）相比，TNM 分期和提名图模型具有更优越的预后性能（一致性指数：训练队列-0.825 vs. 0.603 vs. 0.756，外部验证-0.834 vs. 0.606 vs. 0.789）。重要的是，反应集群在选择可从辅助化疗中获益的候选者方面表现出卓越的能力。总之，基于放射学和生物学反应的动态评估进行风险分层可显著提高对洛杉矶鼻咽癌预后的洞察力，并为个体化治疗的调整提供启示。

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引用次数: 0

Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis 在胰腺导管腺癌模型中靶向抑制 CHKα 和 mTOR：一种治疗转移的新方案。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-28 DOI: 10.1016/j.canlet.2024.217280

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.

胰腺导管腺癌（PDAC）是一种高度转移性恶性肿瘤，目前尚无有效的抗转移疗法。在这里，我们利用单细胞 RNA 测序和代谢组学分析证明，转移细胞高度表达局灶粘附激酶（FAK），FAK 通过重塑胆碱激酶α（CHKα）依赖的胆碱代谢来促进转移。我们设计了一种新型 CHKα 抑制剂 CHKI-03，并在多个临床前模型中验证了其抑制转移的功效。经典的和新合成的小分子抑制剂曾被用于评估在各种动物模型中靶向 mTOR 和 CHKα 的治疗潜力。从机制上讲，FAK激活了mTOR及其下游的HIF-1α，从而提高了CHKα的表达，促进了PDAC细胞的增殖、迁移和侵袭，以及肿瘤的生长和转移。一致的是，FAK 和 CHKα 的高表达水平与 PDAC 患者的不良预后相关。值得注意的是，CHK1-03抑制了CHKα的表达，也抑制了mTORC1的磷酸化，破坏了mTORC1-CHKα的正反馈环路。此外，CHKI-03 和 mTORC1 抑制剂雷帕霉素联合使用可协同抑制 PDX 模型中的肿瘤生长和转移。CHKI-03 和雷帕霉素的联合用药在对吉西他滨耐药的 PDO 模型中显示出相当大的疗效。我们的研究结果揭示了mTORC1-HKα环依赖性胆碱代谢重编程调控PDAC转移的关键机制，凸显了这种新型疗法治疗PDAC转移的治疗潜力。

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引用次数: 0

Corrigendum to “Pin1 inhibition reverses the acquired resistance of human hepatocellular carcinoma cells to Regorafenib via the Gli1/Snail/E-cadherin pathway” [Cancer Lett. 444 (2019) 82–93] 对 "Pin1抑制通过Gli1/Snail/E-cadherin通路逆转人肝癌细胞对瑞戈非尼的获得性抗性 "的更正 [Cancer Lett. 444 (2019) 82-93].

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-27 DOI: 10.1016/j.canlet.2024.217257

引用次数: 0

NSUN4-mediated m5C modification of circERI3 promotes lung cancer development by altering mitochondrial energy metabolism NSUN4 介导的 circERI3 m5C 修饰通过改变线粒体能量代谢促进肺癌发展。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-26 DOI: 10.1016/j.canlet.2024.217266

As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high-throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression in vitro and in vivo was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.

作为一种非常重要的甲基化修饰，5-甲基腺苷（m5C）修饰可通过调节 RNA 的转录、结构和稳定性对其产生深远影响。随着高通量技术的不断发展，差异表达的环状 RNA（circRNA）被越来越多地发现，circRNA 在肿瘤发生和发展中发挥着独特的作用。然而，circRNAs m5C修饰的调控机制尚未被揭示。本研究通过对circRNAs进行差异表达谱分析，初步发现了在肺癌组织中高表达且与肺癌临床进展显著相关的circERI3。结合m5C芯片分析发现，circERI3含有m5C修饰，而NSUN4介导的circERI3的m5C修饰可增加其核输出。阐明了circERI3在体外和体内促进肺癌进展的重要功能。此外，我们还阐明了circERI3靶向DNA结合蛋白1（DDB1），调控其泛素化，增强其稳定性，进而通过DDB1促进过氧化物酶体增殖激活受体γ辅激活子1α（PGC-1α）转录，影响线粒体功能和能量代谢，最终促进肺癌发展的新机制。该研究不仅从甲基化角度揭示了circERI3在肺癌组织中异常分布的原因，阐明了circERI3在肺癌进展中的重要作用，而且描述了circERI3通过线粒体能量代谢促进肺癌发展的新机制，为肺癌中circRNA的研究提供了新的思路。

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引用次数: 0

Unravelling the biological and clinical challenges of circulating tumour cells in epithelial ovarian carcinoma 揭示上皮性卵巢癌循环肿瘤细胞的生物学和临床难题。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-26 DOI: 10.1016/j.canlet.2024.217279

Epithelial ovarian carcinoma (EOC) is the eighth most common cancer in women and the leading cause of gynaecological cancer death, predominantly due to the absence of effective screening tools, advanced stage at diagnosis, and high rates of recurrence. Circulating tumour cells (CTCs), a rare subset of tumour cells that disseminate from a tumour and migrate into the circulation, play a pivotal role in the metastatic cascade, and therefore hold promise as biomarkers for disease monitoring and prognostication. Exploring CTCs from liquid biopsies is an appealing approach for research and clinical practice, given it is minimally invasive, facilitates serial sampling and enables the capture of the entire spectrum of cancer cells circulating in the blood. The prognostic utility of CTC enumeration has been FDA-approved for clinical use in metastatic breast, prostate, and colorectal cancers. However, the unique biology of EOC, discussed herein, compounds the detection and characterisation complexities already inherent in CTC research, consequently hindering progress towards clinical applications. The aim of this review is to provide an overview of both the biological and clinical challenges encountered in harnessing the power of CTCs in EOC.

上皮性卵巢癌（EOC）是女性第八大常见癌症，也是妇科癌症死亡的主要原因，主要是因为缺乏有效的筛查工具、诊断时已是晚期以及复发率高。循环肿瘤细胞（CTCs）是从肿瘤中扩散并迁移到血液循环中的一种罕见的肿瘤细胞亚群，在转移过程中起着关键作用，因此有望成为疾病监测和预后的生物标记物。从液体活检中提取 CTCs 是一种极具吸引力的研究和临床实践方法，因为这种方法创伤极小，便于连续采样，并能捕获血液中循环的所有癌细胞。经 FDA 批准，CTC计数的预后效用可用于转移性乳腺癌、前列腺癌和结直肠癌的临床治疗。然而，本文所讨论的 EOC 的独特生物学特性加剧了 CTC 研究中固有的检测和表征复杂性，从而阻碍了临床应用的进展。本综述旨在概述在 EOC 中利用 CTCs 的威力所遇到的生物学和临床挑战。

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引用次数: 0

Integrated proteomic and glycoproteomic analysis reveals heterogeneity and molecular signatures of brain metastases from lung adenocarcinomas 综合蛋白质组和糖蛋白组分析揭示肺腺癌脑转移瘤的异质性和分子特征

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-26 DOI: 10.1016/j.canlet.2024.217262

Brain metastasis is a major cause of poor prognosis and death in lung adenocarcinoma (LUAD); however, the understanding of therapeutic strategies and mechanisms for brain metastases from LUAD (BM-LUAD) remains notably limited, especially at the proteomics levels. To address this issue, we conducted integrated proteomic and glycoproteomic analyses on 49 BM-LUAD tumors, revealing two distinct subtypes of the disease: BM-S1 and BM-S2. Whole exome sequencing analysis revealed that somatic mutations in STK11 and KEAP1, as well as copy number deletions on chr19p13.3, such as STK11, UQCR11, and SLC25A23, were more frequently detected in BM-S2. In BM-S1 tumors, we observed significant infiltration of GFAP + astrocytes, as evidenced by elevated levels of GFAP, GABRA2, GABRG1 and GAP43 proteins and an enrichment of astrocytic signatures in both our proteomic data and external spatial transcriptomic data. Conversely, BM-S2 tumors demonstrated higher levels of PD-1 immune cell infiltration, supported by the upregulation of PD-1 and LAG-3 genes. These findings suggest distinct microenvironmental adaptations required by the different BM-LUAD subtypes. Additionally, we observed unique glycosylation patterns between the subtypes, with increased fucosylation in BM-S1 and enhanced sialylation in BM-S2, primarily affected by glycosylation enzymes such as FUT9, B4GALT1, and ST6GAL1. Specifically, in BM-S2, these sialylation modifications are predominantly localized to the lysosomes, underscoring the critical role of N-glycosylation in the tumor progression of BM-LUAD. Overall, our study not only provides a comprehensive multi-omic data resource but also offers valuable biological insights into BM-LUAD, highlighting potential mechanisms and therapeutic targets for further investigation.

脑转移是肺腺癌（LUAD）预后不良和死亡的一个主要原因；然而，人们对肺腺癌脑转移（BM-LUAD）的治疗策略和机制的了解仍然非常有限，尤其是在蛋白质组学层面。为了解决这一问题，我们对 49 例 BM-LUAD 肿瘤进行了蛋白质组学和糖蛋白组学综合分析，发现了该疾病的两种不同亚型：BM-S1和BM-S2。全外显子组测序分析表明，STK11和KEAP1的体细胞突变以及chr19p13.3上的STK11、UQCR11和SLC25A23等拷贝数缺失在BM-S2中更为常见。在 BM-S1 肿瘤中，我们观察到 GFAP+星形胶质细胞的显著浸润，这体现在 GFAP、GABRA2、GABRG1 和 GAP43 蛋白水平的升高，以及蛋白质组数据和外部空间转录组数据中星形胶质细胞特征的丰富。相反，BM-S2 肿瘤表现出更高水平的 PD-1 免疫细胞浸润，PD-1 和 LAG-3 基因的上调也支持了这一点。这些发现表明，不同的BM-LUAD亚型需要不同的微环境适应。此外，我们还观察到不同亚型之间独特的糖基化模式，BM-S1 中的岩藻糖基化增加，而 BM-S2 中的硅糖基化增强，这主要是受 FUT9、B4GALT1 和 ST6GAL1 等糖基化酶的影响。具体来说，在 BM-S2 中，这些糖基化修饰主要定位于溶酶体，突出了 N-糖基化在 BM-LUAD 肿瘤进展中的关键作用。总之，我们的研究不仅提供了全面的多组学数据资源，还为 BM-LUAD 提供了有价值的生物学见解，突出了有待进一步研究的潜在机制和治疗靶点。

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引用次数: 0

Revisiting the CXCL13/CXCR5 axis in the tumor microenvironment in the era of single-cell omics: Implications for immunotherapy 在单细胞全息技术时代重新审视肿瘤微环境中的 CXCL13/CXCR5 轴：对免疫疗法的启示

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2024-09-26 DOI: 10.1016/j.canlet.2024.217278

As one of the important members of the family of chemokines and their receptors, the CXCL13/CXCR5 axis is involved in follicle formation in normal lymphoid tissues and the establishment of somatic cavity immunity under physiological conditions, as well as being associated with a wide range of infectious, autoimmune, and tumoral diseases. Here in this review, we focus on its role in tumors. Traditional studies have found the axis to be both pro- and anti-tumorigenic, involving a variety of immune cells, including the tumor cells themselves and those in the tumor microenvironment (TME), and the prognostic significance of this axis is clinical context-dependent. With the development of techniques at the single-cell level, we were able to explain in detail the status of the CXCL13/CXCR5 axis in the TME based on real clinical samples and found that it involves a range of crucial intrinsic anti-tumor immune processes in the TME and is therefore important in tumor immunotherapy. We summarize the cellular subsets, physiological functions, and prognostic significance associated with this axis in the most promising immune checkpoint inhibitor (ICI) therapies of the day and summarize possible therapeutic ideas based on this axis. As with any TME study, the most important takeaway is that the complexity of the CXCL13/CXCR5 axis in TME suggests the importance of personalized therapy in tumor therapy.

作为趋化因子及其受体家族的重要成员之一，CXCL13/CXCR5 轴参与了正常淋巴组织中的滤泡形成和生理条件下体腔免疫的建立，并与多种感染性、自身免疫性和肿瘤性疾病相关。在本综述中，我们将重点讨论它在肿瘤中的作用。传统研究发现，该轴既能促进肿瘤生成，也能抑制肿瘤生成，涉及多种免疫细胞，包括肿瘤细胞本身和肿瘤微环境（TME）中的免疫细胞。随着单细胞水平技术的发展，我们能够根据真实的临床样本详细解释 CXCL13/CXCR5 轴在肿瘤微环境中的状态，并发现它涉及肿瘤微环境中一系列关键的内在抗肿瘤免疫过程，因此在肿瘤免疫疗法中非常重要。我们总结了当前最有前景的免疫检查点抑制剂（ICI）疗法中与该轴相关的细胞亚群、生理功能和预后意义，并总结了基于该轴的可能治疗思路。与任何 TME 研究一样，最重要的启示是 TME 中 CXCL13/CXCR5 轴的复杂性表明了肿瘤治疗中个性化疗法的重要性。

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引用次数: 0