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Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity 表观遗传读者 ZMYND11 的非规范功能限制了 HNRNPA1 介导的应激颗粒形成和致癌活性
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-28 DOI: 10.1038/s41392-024-01961-7
Cheng Lian, Chunyi Zhang, Pan Tian, Qilong Tan, Yu Wei, Zixian Wang, Qin Zhang, Qixiang Zhang, Mengjie Zhong, Li-Quan Zhou, Xisong Ke, Huabing Zhang, Yao Zhu, Zhenfei Li, Jingdong Cheng, Gong-Hong Wei

Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.

表观遗传读取器经常影响基因调控,与疾病预后相关,并具有作为癌症治疗靶点的巨大潜力。锌指 MYND 型含 11(ZMYND11)被公认为可读取表观遗传标记 H3.3K36me3;然而,它在癌症中更广泛的功能和作用机制仍未得到充分探索。在此,我们报告了 ZMYND11 的下调在各种癌症中普遍存在,并且与前列腺癌患者的较差预后密切相关。ZMYND11 的耗竭会促进体外肿瘤细胞的生长、迁移和侵袭,以及体内肿瘤的形成和转移。从机理上讲,我们发现 ZMYND11 依赖于其 MYND 结构域识别精氨酸-194 甲基化的 HNRNPA1,从而将 HNRNPA1 保留在细胞核中,阻止细胞质中应激颗粒的形成,从而发挥抑制肿瘤的作用。此外,ZMYND11 还能抵消 HNRNPA1 驱动的 PKM2/PKM1 比率的增加,从而减轻 PKM2 促进的侵袭性肿瘤表型。值得注意的是,ZMYND11 对 HNRNPA1 的识别可被精氨酸甲基转移酶 PRMT5 的药物抑制所破坏。ZMYND11 低表达的肿瘤对 PRMT5 抑制剂敏感。总之,我们的研究结果揭示了 ZMYND11 作为非组蛋白甲基化阅读器的一种以前未曾探索过的非典型作用,并强调了精氨酸甲基化在 ZMYND11-HNRNPA1 相互作用中对抑制肿瘤进展的至关重要性,从而为癌症治疗提出了新的治疗靶点和潜在的生物标记物。
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引用次数: 0
Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial 舒伐替尼加托瑞帕单抗联合依托泊苷和顺铂作为晚期小细胞肺癌患者的一线治疗:Ib/II期试验
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-27 DOI: 10.1038/s41392-024-01974-2
Yaxiong Zhang, Yan Huang, Yunpeng Yang, Yuanyuan Zhao, Ting Zhou, Gang Chen, Shen Zhao, Huaqiang Zhou, Yuxiang Ma, Shaodong Hong, Hongyun Zhao, Li Zhang, Wenfeng Fang

There is still room for improvement in first-line treatment of advanced small cell lung cancer (SCLC). This trial firstly investigated efficacy and safety of antiangiogenic therapy (surufatinib) (200 mg, qd, po) plus anti-PD-1 treatment (toripalimab) (240 mg, d1, ivdrip) combined with etoposide (100 mg/m², d1-d3, iv, drip) and cisplatin (25 mg/m², d1-d3, ivdrip) for advanced SCLC as first-line treatment, which has been registered on ClinicalTrials.gov under the identifier NCT04996771. The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab. The primary endpoint was progression-free survival (PFS). The secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. All of the 38 patients were enrolled for safety analysis, while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment. After a median follow-up of 21.3 months, the ORR was 97.1% (34/35), and the DCR and the tumor shrinkage rate were both 100% (35/35). The median PFS was 6.9 months (95% CI: 4.6 m–9.2 m) and the median OS was 21.1 months (95% CI: 12.1 m–30.1 m). The 12-month, 18-month, and 24-month OS rates were 66.94%, 51.39% and 38.54%. The occurrence rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 63.2% (24/38), including neutrophil count decreased (31.6%, 12/38), white blood cell count decreased (23.7%, 9/38) and platelet count decreased (10.5%, 4/38). No unexpected adverse events occurred. This novel four-drug regimen (surufatinib, toripalimab, etoposide plus cisplatin) revealed impressive therapeutic efficacy and tolerable toxicities.

晚期小细胞肺癌(SCLC)的一线治疗仍有改进的余地。这项试验首先研究了抗血管生成疗法(索鲁法替尼)(200 毫克,每天三次,每次一粒)加抗 PD-1 疗法(托利帕单抗)(240 毫克,每天一次,每次点滴)联合依托泊苷(100 毫克/平方米,每天一次,每次三粒,每次点滴)和顺铂(25 毫克/平方米,每天一次,每次三粒,每次点滴)作为晚期小细胞肺癌一线治疗的有效性和安全性,该试验已在 ClinicalTrials.gov 上注册,标识符为 NCT04996771。四药治疗方案为4个周期的q3w治疗,同时使用舒伐替尼和托利帕利单抗进行维持治疗。主要终点是无进展生存期(PFS)。次要终点包括客观反应率(ORR)、疾病控制率(DCR)、总生存期(OS)和安全性。所有 38 名患者都被纳入了安全性分析,而只有 35 名患者被纳入了疗效分析,因为有 3 例患者在治疗后失去了疗效评估。中位随访 21.3 个月后,ORR 为 97.1%(34/35),DCR 和肿瘤缩小率均为 100%(35/35)。中位 PFS 为 6.9 个月(95% CI:4.6 个月-9.2 个月),中位 OS 为 21.1 个月(95% CI:12.1 个月-30.1 个月)。12个月、18个月和24个月的OS率分别为66.94%、51.39%和38.54%。≥3级治疗突发不良事件(TEAEs)发生率为63.2%(24/38),包括中性粒细胞计数减少(31.6%,12/38)、白细胞计数减少(23.7%,9/38)和血小板计数减少(10.5%,4/38)。未发生意外不良事件。这种新型四药方案(舒伐替尼、托利帕单抗、依托泊苷加顺铂)疗效显著,毒性可耐受。
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引用次数: 0
A systemic look at pancreatic cancer patients: Predicting metastasis by studying the liver 系统观察胰腺癌患者:通过研究肝脏预测转移
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-27 DOI: 10.1038/s41392-024-01964-4
Susanne Roth, Christoph Michalski, Jörg D. Hoheisel

In a recent paper published in Nature Medicine, Bojmar et al. describe an elaborate effort toward predicting the metastatic progress of pancreatic ductal adenocarcinoma (PDAC) after primary tumour resection.1 Instead of investigating the tumour, however, they studied several molecular, cellular, and metabolic features in biopsy samples from the seemingly still unaffected liver, which were collected during resection of the primary tumour, demonstrating the large and still neglected biomedical potential of looking at cancer in a systemic manner.

在最近发表于《自然医学》(Nature Medicine)上的一篇论文中,Bojmar 等人描述了他们为预测胰腺导管腺癌(PDAC)在原发肿瘤切除后的转移进展所做的精心努力1。然而,他们并没有研究肿瘤,而是研究了在原发肿瘤切除过程中从似乎仍未受影响的肝脏中收集的活检样本中的几种分子、细胞和代谢特征,这表明以系统方式观察癌症具有巨大的、但仍被忽视的生物医学潜力。
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引用次数: 0
Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system 棕榈酰化通过调节中枢神经系统中的 ZDHHC3-Cadm4 轴来调控髓鞘化
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1038/s41392-024-01971-5
Yanli Chang, Jiangli Zhu, Xiaopeng Li, Yi Deng, Birou Lai, Yidan Ma, Jia Tong, Huicong Liu, Juanjuan Li, Chenyu Yang, Qiao Chen, Chengbiao Lu, Yinming Liang, Shiqian Qi, Xiaoning Wang, Eryan Kong

The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

Cadm4(细胞粘附分子 4)的下调是脱髓鞘疾病的一个突出特征,但其潜在的分子机制仍然难以捉摸。在这里,我们发现 Cadm4 在半胱氨酸-347(C347)处发生了特异性棕榈酰化,这对其在质膜(PM)上的稳定定位至关重要。将 C347 突变为丙氨酸(C347A),阻断棕榈酰化,导致 Cadm4 从质膜内化并随后降解。引入 C347A 突变(Cadm4-KI)的体内实验会导致中枢神经系统(CNS)出现严重的髓鞘异常,其特征是髓鞘缺失、脱髓鞘和过度髓鞘化。我们进一步确定 ZDHHC3(锌指 DHHC 型棕榈酰基转移酶 3)是负责催化 Cadm4 棕榈酰化的酶。ZDHHC3 的缺失会降低 Cadm4 的棕榈酰化程度并减少其 PM 定位。值得注意的是,遗传性ZDHHC3缺失会导致Cadm4棕榈酰化减少和中枢神经系统髓鞘化缺陷,与Cadm4-KI小鼠模型类似。因此,Cadm4棕榈酰化的改变会损害Cadm4-KI和ZDHHC3基因敲除小鼠的神经元传递和认知行为。重要的是,ZDHHC3-Cadm4 信号的减弱会显著影响多种脱髓鞘疾病的神经炎症。从机理上讲,我们证明了 Cadm4 在少突胶质细胞系中的主要表达及其通过 WNT-β-Catenin 通路调节细胞分化的潜在作用。综上所述,我们的研究结果表明,ZDHHC3-Cadm4 信号传导失调是导致髓鞘异常的原因之一,这表明与神经炎症相关的脱髓鞘疾病的共同病理机制。
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引用次数: 0
GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia GRP75 触发白色脂肪组织褐变,促进癌症相关恶病质的形成
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1038/s41392-024-01950-w
Xu Chen, Qingnan Wu, Wei Gong, Shaolong Ju, Jiawen Fan, Xiaohan Gao, Xingyang Liu, Xiao Lei, Siqi Liu, Xiangdong Ming, Qianyu Wang, Ming Fu, Yongmei Song, Yan Wang, Qimin Zhan

Cachexia, which affects 50–80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75–ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.

恶病质影响到 50-80% 的癌症患者,是一种使人衰弱的综合征,导致 20% 的癌症相关死亡。恶病质的一个主要特征是脂肪组织萎缩,但人们对脂肪组织如何导致恶病质的发生还知之甚少。在这里,我们在癌症恶病质小鼠模型中证明,白色脂肪组织褐变是一种早期发病的特征性表现,发生在体重减轻和骨骼肌萎缩之前。通过分析来自恶病质诱导肿瘤的细胞外囊泡中不同表达的蛋白质,我们发现了一种分子伴侣--葡萄糖调节蛋白 75(GRP75)--是脂肪细胞褐变的关键介质。从机理上讲,GRP75与腺嘌呤核苷酸转运酶2(ANT2)结合,形成GRP75-ANT2复合物。令人吃惊的是,稳定的 ANT2 会增强与解偶联蛋白 1 的相互作用,导致后者的表达升高,进而促进脂肪细胞褐变。用GRP75抑制剂--卡尼酮(withanone)治疗可逆转这种褐变,并减轻体内的糜烂表型。总之,我们的研究结果揭示了肿瘤衍生的 GRP75 在恶病质发展过程中调节白脂肪组织褐变的新机制,并提出了一种潜在的以白脂肪组织为中心的早期恶病质干预靶向方法。
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引用次数: 0
Characterization of ferroptosis-triggered pyroptotic signaling in heart failure 心力衰竭中铁蛋白沉积触发的热蛋白沉积信号的特征
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1038/s41392-024-01962-6
Xukun Bi, Xiaotian Wu, Jiaqi Chen, Xiaoting Li, Yangjun Lin, Yingying Yu, Xuexian Fang, Xihao Cheng, Zhaoxian Cai, Tingting Jin, Shuxian Han, Meihui Wang, Peidong Han, Junxia Min, Guosheng Fu, Fudi Wang

Pressure overload–induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)–induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

压力过载引起的心脏肥大是心力衰竭(HF)的常见原因,新的证据表明,过多的氧化脂质对心肌细胞具有有害影响。然而,在这一病理过程中,心肌细胞中脂质毒性的关键调节因子仍然未知。在这里,我们利用脂质组学分析和 RNA-seq 分析发现,与假手术小鼠相比,横纹主动脉缩窄(TAC)诱导的高频小鼠体内磷脂酰乙醇胺(PEs)和 Acsl4 的表达显著增加。此外,我们还发现,在心肌细胞中过表达 Acsl4 会通过铁蛋白沉积加剧压力过载诱导的心功能不全。值得注意的是,药理抑制和基因敲除 Acsl4 都能显著缩小 TAC 诱导的高房颤动小鼠的左心室腔大小并改善其心脏功能。此外,在培养的新生大鼠心室肌细胞中沉默 Acsl4 的表达足以抑制肥大刺激诱导的细胞生长。从机理上讲,我们发现依赖于 Acsl4 的铁凋亡激活了热凋亡信号通路,导致促炎细胞因子 IL-1β 的产生增加,中和 IL-1β 可改善 Acsl4 转基因小鼠在 TAC 后的心功能。这些结果表明,在压力过载诱导的心脏重塑过程中,ACSL4 通过铁蛋白沉积诱导的热蛋白沉积信号在心脏中发挥着重要作用。总之,这些研究结果提供了令人信服的证据,表明针对 ACSL4-铁变态反应-热变态反应信号级联可为预防心力衰竭提供一种有前景的治疗策略。
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引用次数: 0
Pre-metastatic niche: formation, characteristics and therapeutic implication 转移前生态位:形成、特征和治疗意义
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1038/s41392-024-01937-7
Yuhang Wang, Jiachi Jia, Fuqi Wang, Yingshuai Fang, Yabing Yang, Quanbo Zhou, Weitang Yuan, Xiaoming Gu, Junhong Hu, Shuaixi Yang

Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.

远处转移是癌症患者死亡的主要原因,也是手术效果不佳的原因之一。在发生器官特异性转移之前,转移前生态位的形成是促进癌细胞扩散的关键。本综述深入探讨了转移前生态位的复杂情况,重点关注肿瘤分泌因子、细胞外囊泡和循环肿瘤细胞在形成转移生态位中的作用。除了肿瘤分泌物质和细胞外囊泡等分子因素外,讨论还将巨噬细胞、中性粒细胞、骨髓抑制细胞和T/B细胞等细胞因素纳入转移前生态位形成的框架。研究还深入探讨了转移前生态位形成的时间机制,如上皮-间质转化、免疫抑制、细胞外基质重塑、代谢重编程、血管通透性和血管生成。此外,还阐明了淋巴结、肺、肝、脑和骨骼等不同转移器官中转移前生态位的情况。重点介绍了针对转移前生态位的细胞和分子成分的治疗方法,以及针对 TGF-β、血管内皮生长因子和 MET 通路等信号通路的干预措施。本综述旨在加深我们对转移前生态位动态的了解,并为制定有效的治疗策略以对抗肿瘤转移提供见解。
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引用次数: 0
Understanding genetics, sex and signaling: Implications of sex-dependent APOE4-neutrophil-microglia interactions for Alzheimer’s and tauopathies 了解遗传学、性别和信号传导:性别依赖性 APOE4-中性粒细胞-小胶质细胞相互作用对阿尔茨海默氏症和牛磺酸病的影响
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1038/s41392-024-01967-1
Natja Haag, Juliane Bremer, Hans Zempel
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引用次数: 0
A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation 了解人类健康和疾病中微生物组的系统框架:从基本原理到临床转化
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1038/s41392-024-01946-6
Ziqi Ma, Tao Zuo, Norbert Frey, Ashraf Yusuf Rangrez

The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the ‘innate and adaptive genomes’, which enhance genetic and evolutionary comprehension of the human genome. The ‘germ-free syndrome’ challenges the traditional ‘microbes as pathogens’ view, advocating for the necessity of microbes for health. The ‘slave tissue’ concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. ‘Acquired microbial immunity’ positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The ‘homeostatic reprogramming hypothesis’ integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The ‘cell-microbe co-ecology model’ elucidates the symbiotic regulation affecting cellular balance, while the ‘meta-host model’ broadens the host definition to include symbiotic microbes. The ‘health-illness conversion model’ encapsulates the innate and adaptive genomes’ interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

人类微生物组是一个复杂而动态的系统,在人类健康和疾病中发挥着重要作用。然而,我们目前对微生物与人类之间错综复杂关系的理解仍存在局限性和理论空白。在这篇叙述性综述中,我们整合了来自解剖学、生理学、免疫学、组织学、遗传学和进化论等不同领域的知识和见解,提出了一个系统性框架。它介绍了 "先天基因组和适应基因组 "等关键概念,这些概念增强了对人类基因组的遗传和进化理解。无菌综合征 "挑战了传统的 "微生物是病原体 "的观点,主张微生物对健康的必要性。从属组织 "概念强调了人体组织与其对应微生物之间错综复杂的共生关系,突出了微生物相互作用对健康的动态影响。获得性微生物免疫 "将微生物组定位为人类免疫系统的辅助工具,为益生菌疗法和谨慎使用抗生素提供了理论依据。稳态重编程假说 "将微生物组纳入内部环境理论,可能解释了工业化后稳态指标的变化。细胞-微生物共生生态学模型 "阐明了影响细胞平衡的共生调节,而 "元宿主模型 "则扩大了宿主的定义,将共生微生物包括在内。健康-疾病转换模型 "概括了先天基因组和适应基因组的相互作用以及菌群失调模式。本文的目的是让人们对微生物组有一个更集中、更一致的认识,并强调未来的研究途径,从而建立一个更有效、更高效的医疗保健系统。
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引用次数: 0
Single-cell exome sequencing reveals polyclonal seeding and TRPS1 mutations in colon cancer metastasis 单细胞外显子组测序揭示结肠癌转移中的多克隆播种和TRPS1突变
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1038/s41392-024-01960-8
Jianqiang Cai, Weilong Zhang, Yalan Lu, Wenjie Liu, Haitao Zhou, Mei Liu, Xinyu Bi, Jianmei Liu, Jinghua Chen, Yanjiang Yin, Yiqiao Deng, Zhiwen Luo, Yi Yang, Qichen Chen, Xiao Chen, Zheng Xu, Yueyang Zhang, Chaoling Wu, Qizhao Long, Chunyuan Huang, Changjian Yan, Yan Liu, Lei Guo, Weihua Li, Pei Yuan, Yucheng Jiao, Wei Song, Xiaobing Wang, Zhen Huang, Jianming Ying, Hong Zhao

Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

肝转移仍然是结肠癌患者死亡的主要原因。确定导致转移的特定驱动基因突变可提供可行的治疗靶点。为了探索转移瘤内的克隆进化和遗传异质性,我们对从一名 IV 期结肠癌患者的原发肿瘤、肝转移瘤和淋巴转移瘤中分离出的 150 个单细胞进行了单细胞外显子测序。肿瘤样本的基因图谱显示,淋巴转移灶和肝转移灶均源自原发肿瘤的同一区域。值得注意的是,肝转移灶直接来自原发肿瘤,绕过了淋巴结。对不同肿瘤内单个细胞对的测序数据进行的比较分析表明,肝转移灶和淋巴转移灶的遗传异质性也大于原发肿瘤。这一发现表明,肝转移瘤和淋巴转移瘤来自多克隆来源的循环肿瘤细胞(CTC)群,而不是来自原发肿瘤的单个细胞。单细胞转录组分析表明,较高的EMT评分和CNV评分与较多的多克隆转移有关。此外,肝转移瘤的单细胞中富含 TRPS1(转录抑制因子 GATA 结合 1)基因突变,即 TRPS1 R544Q。该基因突变通过 TRPS1R544Q/ZEB1 轴,明显增加了 CRC 在体外和体内的侵袭和迁移。在更多的结肠癌病例中检测到了更多的TRPS1突变,这些突变与晚期疾病和不良预后相关。这些结果揭示了多克隆播种和TRPS1突变是结肠癌肝转移发展的潜在驱动机制。
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Signal Transduction and Targeted Therapy
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