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Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice. 通过新型锂有机配位化合物靶向调控 USP11 可改善阿尔茨海默氏症转基因小鼠的神经病理学和认知功能。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-11 DOI: 10.1038/s44321-024-00146-7
Yi Guo, Chuanbin Cai, Bingjie Zhang, Bo Tan, Qinmin Tang, Zhifeng Lei, Xiaolan Qi, Jiang Chen, Xiaojiang Zheng, Dan Zi, Song Li, Jun Tan

Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.

阿尔茨海默病(AD)是全球最常见的神经退行性疾病,严重损害患者的认知功能。虽然其确切病因尚不清楚,但错误折叠的β-淀粉样肽和tau蛋白的异常聚集被认为是其病理发展的关键。最近的研究发现,泛素特异性蛋白酶11(USP11)是tau去泛素化的关键调节因子,会加剧tau的聚集和AD的病理变化。因此,通过阻断USP11活性或降低USP11蛋白水平来抑制USP11功能,可作为一种有效的AD治疗策略。我们的研究引入了一种独特的异丁烯酸锂-L-脯氨酸配位化合物 IsoLiPro,它能有效降低 USP11 蛋白水平并增强体外 tau 泛素化。此外,长期口服 IsoLiPro 能显著降低 AD 转基因小鼠的总 tau 和磷酸化 tau 水平。此外,IsoLiPro 还能显著减少 β 淀粉样蛋白沉积和突触损伤,改善这些动物模型的认知功能。这些结果表明,IsoLiPro 作为一种新型小分子 USP11 抑制剂,能有效缓解 AD 类病理现象并改善认知功能,有望成为一种潜在的多靶点 AD 治疗药物。
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引用次数: 0
Diagnosing and engineering gut microbiomes. 诊断和改造肠道微生物组。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-28 DOI: 10.1038/s44321-024-00149-4
Elisa Cappio Barazzone, Médéric Diard, Isabelle Hug, Louise Larsson, Emma Slack

The microbes, nutrients and toxins that we are exposed to can have a profound effect on the composition and function of the gut microbiome. Thousands of peer-reviewed publications link microbiome composition and function to health from the moment of birth, right through to centenarians, generating a tantalizing glimpse of what might be possible if we could intervene rationally. Nevertheless, there remain relatively few real-world examples where successful microbiome engineering leads to beneficial health effects. Here we aim to provide a framework for the progress needed to turn gut microbiome engineering from a trial-and-error approach to a rational medical intervention. The workflow starts with truly understanding and accurately diagnosing the problems that we are trying to fix, before moving on to developing technologies that can achieve the desired changes.

我们接触的微生物、营养物质和毒素会对肠道微生物组的组成和功能产生深远影响。成千上万篇经同行评审的论文将微生物组的组成和功能与健康联系在一起,从婴儿出生到百岁老人,让人看到了如果我们能够合理干预可能实现的前景。然而,在现实世界中,成功的微生物组工程对健康产生有益影响的例子仍然相对较少。在此,我们旨在为将肠道微生物组工程从试错方法转变为理性医疗干预所需的进展提供一个框架。工作流程首先要真正理解并准确诊断我们试图解决的问题,然后再开发能够实现预期变化的技术。
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引用次数: 0
Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors. 实体瘤中对胎盘糖胺聚糖具有特异性的瞬时 CAR T 细胞。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-15 DOI: 10.1038/s44321-024-00153-8
Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard

Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be "armed" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.

由于糖表位的复杂性和获得特异亚型结合的选择有限,糖胺聚糖通常被排除在合成免疫疗法靶点的优先考虑之外。实体瘤表达的蛋白多糖是由胎盘上的硫酸软骨素(CS)修饰的,这种修饰通常仅限于胎盘。在这里,我们报告了对胎盘上硫酸软骨素具有选择性的瞬时嵌合抗原受体(CAR)T 细胞的设计和功能。在 T 细胞中表达后,CAR 可以用重组 VAR2CSA 凝集素(rVAR2)"武装",以靶向表达胎盘上 CS 的肿瘤细胞。未装备的 CAR T 细胞在靶细胞存在的情况下仍然没有活性,而装备了 VAR2 的 CAR T 细胞则显示出强大的活化能力,并能在体外消除不同类型的肿瘤细胞。CAR T细胞的细胞毒性与CAR可用的rVAR2浓度成正比,这为微调CAR T细胞活性提供了一种潜在的分子处理方法。在体内,武装的 CAR T 细胞能迅速靶向膀胱肿瘤,并提高肿瘤小鼠的存活率。因此,我们的研究表明,癌症限制性糖胺聚糖可被用作 CAR T 细胞疗法的潜在靶点。
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引用次数: 0
A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import. 能特异性阻断 HIV-1 核导入的新型帽状体靶向抑制剂。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1038/s44321-024-00143-w
Aude Boulay, Emmanuel Quevarec, Isabelle Malet, Giuseppe Nicastro, Célia Chamontin, Suzon Perrin, Corinne Henriquet, Martine Pugnière, Valérie Courgnaud, Mickaël Blaise, Anne-Geneviève Marcelin, Ian A Taylor, Laurent Chaloin, Nathalie J Arhel

HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC50. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import.

HIV-1 包囊通过与核导入机制结合穿过核孔复合体(NPC)。为了找出能抑制 HIV-1 核导入的化合物,我们在运输蛋白-1(TRN-1)结合的 CA 六聚体三维模型上进行了药物筛选。其中,化合物 H27 以较低的微摩尔 IC50 值抑制了 HIV-1。与其他 CA 靶向化合物不同的是,H27 不会改变 CA 的组装或分解,能特异性地抑制核导入,并对 PF74 和来那卡韦耐药突变体保持抗病毒活性。不同灵长类慢病毒噬菌体的不同敏感性、噬菌体稳定性和 H27 逃逸突变体以及结构分析表明,H27 与组装的噬菌体有多种低亲和力接触。相互作用实验表明,H27 可能通过阻止 CA 与 TRN-1 等 NPC 机制成分接触而发挥作用。H27 在体内表现出良好的代谢稳定性,对不同亚型、来自治疗无效患者的循环重组型以及对四大类抗逆转录病毒药物耐药的菌株均有效。这项工作确定了通过特异性阻断 HIV-1 核导入而展示新型作用机制的化合物。
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引用次数: 0
Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects. Jag1不足会通过T细胞和肝细胞分化缺陷改变肝纤维化。
IF 11.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1038/s44321-024-00145-8
Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson

Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

纤维化有助于组织修复,但过度纤维化会破坏器官功能。Alagille 综合征(ALGS,由 JAGGED1 基因突变引起)会导致肝脏疾病和特征性纤维化。在这里,我们发现作为 ALGS 模型的 Jag1Ndr/Ndr 小鼠再现了类似 ALGS 的纤维化。肝脏的单细胞RNA-seq和多色流式细胞术显示,尽管Jag1Ndr/Ndr小鼠存在胆汁淤积,但肝细胞尚未发育成熟,肝内T细胞浸润却很低。对胸腺和脾脏调节性 T 细胞(Tregs)进行了富集,并将 Jag1Ndr/Ndr 淋巴细胞免疫和纤维化能力通过收养性转移到 Rag1-/- 小鼠体内进行了测试,这些小鼠受到了葡聚糖硫酸钠(DSS)或胆管结扎(BDL)的挑战。与 Jag1+/+ 淋巴细胞相比,移植的 Jag1Ndr/Ndr 淋巴细胞对 DSS 的炎症反应较轻,活化的 T 细胞较少。在Rag1-/-小鼠体内移植了Jag1Ndr/Ndr淋巴细胞后,BDL诱导的胆汁淤积导致小鼠肾门周围Treg聚集,肾门周围纤维化程度是移植了Jag1+/+淋巴细胞的Rag1-/-小鼠的三倍。最后,Jag1Ndr/Ndr 肝细胞的表达谱和 Treg 的过度代表性在患者的肝脏样本中得到了证实。因此,依赖于 Jag1 的肝脏和免疫缺陷相互作用,决定了 ALGS 的纤维化过程。
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引用次数: 0
Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis. 乳腺癌会分泌抗发酵的 MUFAs,并依赖硒蛋白合成实现转移。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-21 DOI: 10.1038/s44321-024-00142-x
Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito

The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

三阴性乳腺癌(TNBC)患者的治疗方案有限,导致转移性复发率高、预后差。铁中毒是一种由铁依赖的脂质过氧化引起的细胞死亡,硒蛋白 GPX4 的抗氧化活性可抵消铁中毒。在这里,我们发现 TNBC 细胞在高密度培养时会在细胞外环境中分泌一种抗铁细胞凋亡因子,但在低密度形成集落时则会发生铁细胞凋亡。我们发现,含有单不饱和脂肪酸(MUFA)的脂质是抗铁中毒因子的分泌物,单细胞是否容易发生铁中毒取决于硬脂酰-CoA 去饱和酶(SCD)的低表达量,而这种表达量与细胞密度成正比。最后,我们表明,Sec-tRNAsec 生物合成是产生硒蛋白的一个重要步骤,它的抑制会导致铁变态反应,并损害循环 TNBC 细胞的肺部播种,这些细胞不再受到原发肿瘤富含 MUFA 环境的保护。
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引用次数: 0
Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus. 脑外膜细胞系重编程作为治疗脑积水的一种潜在干预措施。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-28 DOI: 10.1038/s44321-024-00156-5
Konstantina Kaplani, Maria-Eleni Lalioti, Styliani Vassalou, Georgia Lokka, Evangelia Parlapani, Georgios Kritikos, Zoi Lygerou, Stavros Taraviras

Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.

脑积水是一种常见的神经系统疾病,其特点是脑脊液在脑室过度积聚。脑积水的主要治疗方法是通过神经外科手术进行脑脊液引流,但这种方法的发病率和失败率都很高,因此有必要探索新的治疗方法。虽然脑积水的病理生理学具有高度的多因素性,但脑外膜细胞功能受损在脑积水中起着根本性的作用。在这里,我们发现 GemC1 和 McIdas(多纤毛外膜细胞命运决定的关键调控因子)可诱导细胞直接向外膜重编程。我们的研究发现,异位表达GemC1和McIdas可以重编程大脑皮层星形胶质细胞,并将小鼠胚胎干细胞编程为外膜。McIdas足以在重编程的星形胶质细胞中建立功能活性。此外,我们还发现,McIdas的表达可促进两种不同的出生后脑积水小鼠模型(颅内出血和遗传性脑积水)中的外膜细胞再生,并改善神经源龛的细胞结构。我们的研究提供了在模拟脑积水的动物模型中恢复外膜的证据,可用于未来的治疗干预。
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引用次数: 0
Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice. 叶黄素通过降解小鼠体内的 Uroc1 蛋白,为 DEHP 解毒并防止肝损伤。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-29 DOI: 10.1038/s44321-024-00160-9
Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen

Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.

邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种环境污染物,在环境和临床样本中被广泛检测到,对内分泌系统的平衡构成严重威胁。DEHP 在肝脏中的蓄积尤为明显,可导致肝损伤。由于缺乏有效的高通量筛选系统,阻碍了能特异性靶向消除 DEHP 有害影响的药物的发现。在这里,通过开发一种基于Cy5修饰的单链DNA-aptamer方法来靶向DEHP,我们发现了木犀草素这种潜在的药物,它通过促进小鼠原代肝细胞和肝脏中DEHP的排出,在DEHP的解毒方面显示出强大的功效。从机理上讲,木犀草素通过靶向肝脏尿氨酸水解酶1(Uroc1)的Ala270和Val272位点,促进其蛋白质降解。更重要的是,反式尿囊酸(trans-UCA)作为 Uroc1 的底物,通过抑制 ERK1/2 信号级联调节溶酶体的外泌,具有与叶黄素类似的特性。总之,通过调节 UCA/Uroc1 轴,木犀草素可作为一种有效的治疗药物,在肝脏中有效地解毒 DEHP。
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引用次数: 0
Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer. NOTCH和SOX2的相互抑制塑造了肿瘤细胞的可塑性和三阴性乳腺癌的治疗逃逸。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00161-8
Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke

Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.

癌细胞可塑性是三阴性乳腺癌(TNBC)化疗和靶向治疗失败的重要原因。治疗诱导的肿瘤细胞可塑性及相关耐药性的分子机制在很大程度上尚属未知。通过全基因组 CRISPR-Cas9 筛选,我们研究了用γ-分泌酶抑制剂(GSI)治疗 NOTCH 驱动的 TNBC 的逃逸机制,并确定 SOX2 为 Notch 抑制的耐药靶点。我们描述了Notch信号传导与SOX2之间一种新型的相互抑制反馈机制。具体来说,Notch信号通过其HEY家族的靶基因抑制SOX2的表达,而SOX2则通过与RBPJ的直接相互作用抑制Notch信号。这种机制形成了不同的细胞状态,Notch 阳性的 TNBC 更像上皮细胞,而 SOX2 的表达则与上皮-间质转化相关,诱导癌症干细胞特征和 GSI 抗性。为了应对单药治疗诱导的肿瘤复发,我们分别在对NOTCH抑制剂敏感和耐药的TNBC异种移植中评估了GSI-紫杉醇和达沙替尼-紫杉醇联合疗法。这些不同的预防性组合和二线治疗方案依赖于 TNBC 中 NOTCH1 和 SOX2 的表达,能够诱导肿瘤生长控制并减少转移负荷。
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引用次数: 0
Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection. 将循环细胞游离线粒体 DNA 的异常片段组特征作为检测多种癌症的新型生物标记物。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-30 DOI: 10.1038/s44321-024-00163-6
Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing

Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.

人们对循环游离细胞线粒体 DNA(ccf-mtDNA)的片段组学特征,包括片段轮廓、5'端碱基偏好和基序多样性知之甚少。在此,我们利用基于捕获的新一代测序技术,对1607份血浆样本进行了ccf-mtDNA测序。我们首先发现,ccf-mtDNA的片段组特征与循环细胞游离核DNA的片段组特征明显不同。此外,我们还观察到ccf-mtDNA的区域特异性片段组特征,这与线粒体DNA的蛋白质结合、碱基组成和特殊结构有关。与非癌症对照组相比,六种癌症患者表现出异常片段组特征。然后,根据片段组特征建立了癌症检测模型。内部和外部验证组群都证明了我们的模型在区分癌症患者和非癌症对照组方面的卓越能力,所有模型的曲线下面积都高于 0.9322。在两个验证队列中,六种癌症类型的原发组织总体准确率分别为 89.24% 和 87.92%。总之,我们的研究全面描述了ccf-mtDNA的癌症特异性片段组学特征,为基于ccf-mtDNA片段组学的多癌症检测和原发组织分类提供了原理性证明。
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引用次数: 0
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EMBO Molecular Medicine
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