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Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability. 集导管癌的全面分子特征描述,寻找治疗漏洞。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1038/s44321-024-00102-5
Peiyong Guan, Jianfeng Chen, Chengqiang Mo, Tomoya Fukawa, Chao Zhang, Xiuyu Cai, Mei Li, Jing Han Hong, Jason Yongsheng Chan, Cedric Chuan Young Ng, Jing Yi Lee, Suet Far Wong, Wei Liu, Xian Zeng, Peili Wang, Rong Xiao, Vikneswari Rajasegaran, Swe Swe Myint, Abner Ming Sun Lim, Joe Poh Sheng Yeong, Puay Hoon Tan, Choon Kiat Ong, Tao Xu, Yiqing Du, Fan Bai, Xin Yao, Bin Tean Teh, Jing Tan

Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

集合管癌(CDC)是一种侵袭性罕见肾癌亚型,其临床需求尚未得到满足。由于其罕见性和缺乏临床前模型,人们对其潜在的分子改变和病因知之甚少。本研究旨在全面描述 CDC 的分子改变特征,并确定其治疗弱点。通过全外显子组和转录组测序,我们在 3/13 例(23%)患者中发现了 KRAS 热点突变(G12A/D/V),此外还有已知的 TP53 和 NF2 突变。3/13(23%)例患者携带由马兜铃酸(AA)暴露引起的突变特征(SBS22),众所周知,这种突变在亚洲更为普遍,这凸显了该病的地质特异性病因。我们进一步发现,细胞周期相关通路是最主要的失调通路。我们利用新建立的 CDC 临床前模型进行了药物筛选,发现 CDK9 抑制剂 LDC000067 能特异性抑制 CDC 肿瘤的生长并延长存活时间。我们的研究不仅增进了我们对亚洲 CDC 致癌性分子改变的了解,还发现细胞周期机制是治疗的薄弱环节,为治疗此类侵袭性癌症患者的临床试验奠定了基础。
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引用次数: 0
Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites. 通过单剂量孢子虫注射血期减毒疟原虫进行实验性疫苗接种。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00101-6
Julia M Sattler, Lukas Keiber, Aiman Abdelrahim, Xinyu Zheng, Martin Jäcklin, Luisa Zechel, Catherine A Moreau, Smilla Steinbrück, Manuel Fischer, Chris J Janse, Angelika Hoffmann, Franziska Hentzschel, Friedrich Frischknecht

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

目前正在探索利用疟原虫活体接种疟疾疫苗的方法,即利用减毒的蚊源性孢子虫或减毒的血期寄生虫。这两种方法都将得益于可获得血期繁殖率降低的减毒和无毒寄生虫。在这里,我们筛选了生长缓慢的啮齿类寄生虫 P. berghei 和人类寄生虫 P. falciparum 的基因缺失突变体。此外,我们还测试了伯格希氏疟原虫突变体的无毒性和解决血期感染的能力,同时保留了孢子虫的形成和肝脏感染。以 51 个基因为靶标,产生了 18 个伯格氏疟原虫基因缺失突变体,其中几个突变体可引起轻度感染。两种最弱的突变体的血液阶段感染或孢子虫感染都能被免疫反应清除。对小鼠进行免疫可使其在受到野生型孢子虫挑战后免于发病。六种恶性疟原虫基因缺失突变体中有两种生长速度缓慢。生长缓慢、无毒的恶性疟原虫突变体将成为诱导免疫反应的宝贵工具,有助于开发新的寄生虫减毒疫苗并保护现有疫苗。
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引用次数: 0
Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction. 通过全基因组测序和单线程纠错技术进行超灵敏残留疾病分子检测。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI: 10.1038/s44321-024-00115-0
Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando L Mendez, Yingyu Wang, Paul Tang, Qianqian Yao, Marcus W Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

虽然无细胞 DNA(cfDNA)全基因组测序(WGS)在检测分子残留疾病(MRD)方面前景广阔,但其性能却受到 WGS 错误率的限制。在这里,我们介绍一种高效的 cfDNA WGS 技术 AccuScan,它能在单个读数级实现全基因组纠错,错误率为 4.2 × 10-7,比以读数为中心的去噪方法低两个数量级。AccuScan 在 MRD 中的应用表明,其分析灵敏度低至 10-6 循环变异等位基因频率,样本级特异性高达 99%。AccuScan 在预测结直肠癌复发方面显示出 90% 的标志性灵敏度(术后 6 周内)和 100% 的特异性。使用术后一周内采集的样本,AccuScan 对食管癌也显示出 67% 的灵敏度和 100% 的特异性。当 AccuScan 用于监测黑色素瘤患者的免疫疗法时,循环肿瘤 DNA (ctDNA) 水平和动态轮廓与临床结果一致。总之,AccuScan 为 MRD 检测提供了高精度的 WGS 解决方案,可在百万分之一的范围内检测 ctDNA,无需大量样本输入或个性化试剂。
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引用次数: 0
Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy. 恢复神经元亚群的氧化磷酸化缺陷可预防线粒体脑病。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1038/s44321-024-00111-4
Brittni R Walker, Lise-Michelle Theard, Milena Pinto, Monica Rodriguez-Silva, Sandra R Bacman, Carlos T Moraes

Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5-6 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.

氧化磷酸化(OXPHOS)缺陷可导致严重的脑病,目前还没有治疗这些疾病的有效方法。为了评估基因替代预防疾病进展的能力,我们对两种不同的中枢神经系统缺陷小鼠模型(Ndufs3/复合体I或Cox10/复合体IV条件性基因敲除)进行了基因治疗。我们使用经腹腔注射的 AAV-PHP.eB 将缺失基因送入这些小鼠的中枢神经系统。在这两种情况下,我们观察到小鼠的存活期从 5-6 个月延长到 15 个月以上,而且没有发现疾病表型。同样,接受治疗的小鼠的分子和细胞表型也基本恢复。令人惊讶的是,在所用条件下,只有约30%的神经元表达了AAV-PHP.eB载体的转基因,却实现了这些显著的表型改善。这些研究结果表明,缺乏 OXPHOS 的神经元会受到周围神经元环境的保护,而部分补偿神经元 OXPHOS 的缺失会产生不成比例的积极影响。
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引用次数: 0
Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment. 丹曲林可纠正达里尔病的细胞疾病特征,可能是一种新型疗法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI: 10.1038/s44321-024-00104-3
Matthew Hunt, Nuoqi Wang, Naricha Pupinyo, Philip Curman, Monica Torres, William Jebril, Maria Chatzinikolaou, Julie Lorent, Gilad Silberberg, Ritu Bansal, Teresa Burner, Jing Zhou, Susanne Kimeswenger, Wolfram Hoetzenecker, Keith Choate, Etty Bachar-Wikstrom, Jakob D Wikstrom

Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.

达里尔病(Darier disease,DD)是一种罕见的严重棘层溶解性皮肤病,由编码肌浆/内质网钙ATP酶同工酶2(SERCA2)的ATP2A2基因突变引起。SERCA2 通过将钙泵入内质网维持内质网钙平衡,对调节细胞钙动力学和细胞功能至关重要。迄今为止,还没有专门针对 DD 疾病机制的治疗方法。丹曲林钠(Dl)是一种雷诺丁受体拮抗剂,可抑制ER的钙释放,从而提高ER的钙水平,目前用于非皮肤病适应症。在这项研究中,我们首先确定了 DD 患者皮肤中失调的基因和分子通路,显示了细胞粘附和钙平衡通路的下调,以及 ER 应激和细胞凋亡的上调。然后,我们在各种体外 DD 模型和 SERCA2 抑制模型中表明,Dl 有助于保留 ER 钙并促进细胞粘附。此外,Dl 处理可降低 ER 压力并抑制细胞凋亡。我们的研究结果表明,Dl 能特异性地针对 DD 的致病机制,可能是一种潜在的治疗方法。
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引用次数: 0
The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis. ASC 炎性体适配器在炎性淀粉样变性中控制 SAA 衍生蛋白的聚集。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00107-0
Marco Losa, Marc Emmenegger, Pierre De Rossi, Patrick M Schürch, Tetiana Serdiuk, Niccolò Pengo, Danaëlle Capron, Dimitri Bieli, Niklas Bargenda, Niels J Rupp, Manfredi C Carta, Karl J Frontzek, Veronika Lysenko, Regina R Reimann, Petra Schwarz, Mario Nuvolone, Gunilla T Westermark, K Peter R Nilsson, Magdalini Polymenidou, Alexandre Pa Theocharides, Simone Hornemann, Paola Picotti, Adriano Aguzzi

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.

细胞外释放的分子炎症小体集合体--ASC斑点--在阿尔茨海默病中交叉播散Aβ淀粉样蛋白。这是一种在慢性炎症条件下由急性期反应物血清淀粉样蛋白 A(SAA)的聚集和外周沉积引起的全身性疾病。我们利用超分辨率显微镜发现,在人类 AA 淀粉样变性中,ASC 与 SAA 紧密共聚焦。重组 ASC斑点加速了SAA纤维的形成,有限蛋白水解后的质谱分析表明,ASC通过其吡啶结构域(PYD)与SAA相互作用。在炎症性 AA 淀粉样变性小鼠模型中,缺乏 ASC 的 Pycard-/- 小鼠脾脏淀粉样蛋白负荷明显减少。用抗ASCPYD抗体治疗可减少AA淀粉样变性野生型小鼠的淀粉样蛋白负荷。在19334名医院患者中,天然抗ASC IgG(-logEC50 ≥ 2)的流行率为
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引用次数: 0
Publisher Correction: LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition. 出版商更正:LKB1-SIK2 缺失促使葡萄膜黑色素瘤增殖并对 SLC8A1 和 ROS 抑制剂过敏。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 DOI: 10.1038/s44321-024-00114-1
Sarah Proteau, Imène Krossa, Chrystel Husser, Maxime Guéguinou, Federica Sella, Karine Bille, Marie Irondelle, Mélanie Dalmasso, Thibault Barouillet, Yann Cheli, Céline Pisibon, Nicole Arrighi, Sacha Nahon-Estève, Arnaud Martel, Lauris Gastaud, Sandra Lassalle, Olivier Mignen, Patrick Brest, Nathalie M Mazure, Frédéric Bost, Stéphanie Baillif, Solange Landreville, Simon Turcotte, Dan Hasson, Saul Carcamo, Christophe Vandier, Emily Bernstein, Laurent Yvan-Charvet, Mitchell P Levesque, Robert Ballotti, Corine Bertolotto, Thomas Strub
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引用次数: 0
The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas. 依赖于MondoA的TXNIP/GDF15轴可预测结直肠腺癌的奥沙利铂反应。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00105-2
Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose M Vicencio, Petra Vlckova, Yue Chen, James Monypenny, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthy, Xiaoping Yang, Zedong Hu, Joanna C Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

化疗是晚期癌症患者的标准治疗方法,越来越多的人认识到化疗能激活宿主免疫反应,从而产生持久的疗效。在这里,我们在结直肠腺癌(CRC)中发现了奥沙利铂诱导的硫氧还蛋白相互作用蛋白(TXNIP),这是一种依赖于蒙多A的肿瘤抑制基因,是生长/分化因子15(GDF15)的负调控因子。GDF15 是 CRC 的负预后因子,能促进调节性 T 细胞(Tregs)的分化,从而抑制 CD8 T 细胞的活化。耐人寻味的是,包括患者衍生肿瘤器官组织在内的多种模型表明,TXNIP 和 GDF15 对奥沙利铂反应性的丧失与疾病晚期或化疗耐药有关,转录组或蛋白质组 GDF15/TXNIP 比率显示出作为预后生物标志物的潜力。这些发现说明了化疗诱导的上皮氧化应激驱动局部免疫重塑使患者获益的潜在共同途径,在难治或晚期病例中会出现这种途径的破坏。
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引用次数: 0
Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer. 针对胃癌致癌融合基因 CLDN18-ARHGAP 的免疫疗法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI: 10.1038/s44321-024-00120-3
Yue Wang, Hanbing Wang, Tao Shi, Xueru Song, Xin Zhang, Yue Zhang, Xuan Wang, Keying Che, Yuting Luo, Lixia Yu, Baorui Liu, Jia Wei

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

CLDN18-ARHGAP融合基因是胃癌中新发现的致癌驱动基因。本中心在9%(8/87)的胃癌患者中检测到了该基因。我们生成了一种特异性靶向 CLDN18-ARHGAP 融合基因的免疫原性多肽来诱导新抗原反应性 T 细胞,在体外细胞培养模型和体内异种移植胃癌模型中均被证明具有特异性和强大的抗肿瘤能力。除了免疫原性潜力外,研究还发现CLDN18-ARHGAP融合基因还能通过诱导调节性T(Treg)细胞富集的微环境来促进免疫抑制。从机制上讲,CLDN18-ARHGAP融合基因的胃癌细胞会激活PI3K/AKT-mTOR-FAS信号转导,从而增强胃癌细胞的游离脂肪酸生成,有利于Treg细胞的存活。此外,抑制 PI3K 可有效逆转 Treg 细胞的上调,从而增强体外新抗原反应 T 细胞的抗肿瘤细胞毒性,并降低异种移植胃癌模型中的肿瘤生长。我们的研究发现,CLDN18-ARHGAP融合基因是免疫原性新表位的重要来源,是肿瘤免疫微环境的关键调节因子,以及针对这种致癌融合基因的免疫治疗应用。
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引用次数: 0
DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells. DiPRO1 可对肌肉和间质癌细胞进行独特的重编程。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1038/s44321-024-00097-z
Jeremy Rich, Melanie Bennaroch, Laura Notel, Polina Patalakh, Julien Alberola, Fayez Issa, Paule Opolon, Olivia Bawa, Windy Rondof, Antonin Marchais, Philippe Dessen, Guillaume Meurice, Morgane Le-Gall, Melanie Polrot, Karine Ser-Le Roux, Kamel Mamchaoui, Nathalie Droin, Hana Raslova, Pascal Maire, Birgit Geoerger, Iryna Pirozhkova

We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.

最近,我们发现了一种尚未定性的 ZNF555 蛋白,它是参与面岬肱肌营养不良症中 4qA 基因座病态功能的生产性复合物的一个组成部分。我们的研究提供了大量证据,证明它在人类肌母细胞的分化和增殖过程中发挥作用。DiPRO1 通过肌生成主调节因子 SIX1 的调节结合区发挥作用。DiPRO1 通过表观遗传调节因子 TIF1B 和 UHRF1 发挥抑制作用,维持顺式调节元件和基因启动子的甲基化。DiPRO1 的缺失会模拟宿主对病毒的防御反应,唤醒逆转录可重复序列和 ZNF/KZFP 基因家族。这样就能消灭癌细胞,通过NF-kappaB信号控制TNF-α,重新规划细胞决策平衡,使其趋向炎症和/或凋亡。最后,我们的研究结果突显了间质癌肿瘤对基于 si/shDiPRO1 的纳米药物的脆弱性,从而将 DiPRO1 定位为潜在的治疗靶点。
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