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Let it be: Preserving tumor-draining lymph nodes in the era of immuno-oncology 顺其自然:在免疫肿瘤学时代保留肿瘤引流淋巴结
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.015
Robert Saddawi-Konefka, Shiruyeh Schokrpur, J. Silvio Gutkind

Solid cancers often progress via metastasis to lymph nodes. Consequently, lymphadenectomy is central to stage cancers and eradicates disease spread. However, mounting evidence suggests that cancer immunotherapies drive antitumor immune responses within lymph nodes. This implies that immunotherapy, delivered with standard oncologic therapies, may require specific treatment sequencing to initiate immunosurveillance and affect primary tumor responses. As supported by recent preclinical and clinical studies, lymphatic-preserving strategies may offer the best promise for driving the next generation of breakthrough immunotherapy approaches.

实体瘤通常通过淋巴结转移发展。因此,淋巴结切除术是癌症分期和根除疾病扩散的关键。然而,越来越多的证据表明,癌症免疫疗法会在淋巴结内产生抗肿瘤免疫反应。这意味着,与标准肿瘤疗法同时进行的免疫疗法可能需要特定的治疗顺序,以启动免疫监视并影响原发性肿瘤反应。最近的临床前和临床研究表明,淋巴保留策略最有希望推动下一代突破性免疫疗法的发展。
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引用次数: 0
Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. 腔棘肽(cavtratin)对肿瘤微血管通透性的选择性抑制可阻止小鼠的肿瘤进展。
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-10 Epub Date: 2024-05-30 DOI: 10.1016/j.ccell.2024.05.009
Jean-Philippe Gratton, Michelle I Lin, Jun Yu, Erik D Weiss, Zao Li Jiang, Todd A Fairchild, Yasuko Iwakiri, Roberto Groszmann, Kevin P Claffey, Yung-Chi Cheng, William C Sessa
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引用次数: 0
RNA vaccines for cancer: Principles to practice 治疗癌症的 RNA 疫苗:从原理到实践
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-06 DOI: 10.1016/j.ccell.2024.05.005
Pablo Guasp, Charlotte Reiche, Zachary Sethna, Vinod P. Balachandran

Vaccines are the most impactful medicines to improve health. Though potent against pathogens, vaccines for cancer remain an unfulfilled promise. However, recent advances in RNA technology coupled with scientific and clinical breakthroughs have spurred rapid discovery and potent delivery of tumor antigens at speed and scale, transforming cancer vaccines into a tantalizing prospect. Yet, despite being at a pivotal juncture, with several randomized clinical trials maturing in upcoming years, several critical questions remain: which antigens, tumors, platforms, and hosts can trigger potent immunity with clinical impact? Here, we address these questions with a principled framework of cancer vaccination from antigen detection to delivery. With this framework, we outline features of emergent RNA technology that enable rapid, robust, real-time vaccination with somatic mutation-derived neoantigens—an emerging “ideal” antigen class—and highlight latent features that have sparked the belief that RNA could realize the enduring vision for vaccines against cancer.

疫苗是改善健康状况最具影响力的药物。虽然疫苗对病原体有很强的抵抗力,但癌症疫苗仍是一个尚未实现的承诺。然而,近来 RNA 技术的进步以及科学和临床上的突破推动了肿瘤抗原的快速发现和有效传递,使癌症疫苗的前景变得诱人。然而,尽管目前正处于关键时刻,一些随机临床试验也将在未来几年逐渐成熟,但仍存在几个关键问题:哪些抗原、肿瘤、平台和宿主可以触发具有临床影响的强效免疫?在此,我们通过一个从抗原检测到递送的癌症疫苗接种原则框架来解决这些问题。在这一框架下,我们概述了新兴 RNA 技术的特点,这些特点使体细胞突变衍生的新抗原--一种新兴的 "理想 "抗原--能够实现快速、稳健、实时的疫苗接种,并强调了激发人们相信 RNA 可以实现癌症疫苗持久愿景的潜在特点。
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引用次数: 0
Engineering cancer’s end: An interdisciplinary approach to confront the complexities of cancer 工程学终结癌症:应对癌症复杂性的跨学科方法
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-06 DOI: 10.1016/j.ccell.2024.05.017
Elsa R. Flores, W. Gregory Sawyer

Cancer engineering is an interdisciplinary approach that promises to confront the complexities of cancer and accelerate transformative discoveries by integrating innovative fields across engineering and the physical sciences with a focus on cancer. We offer a conceptual framework for the hallmarks of cancer engineering, integrating 12 fields: system dynamics; imaging, radiation, and spectroscopy; robotics and controls; solid mechanics; fluid mechanics; chemistry and nanomaterials; mathematics and simulation; cellular and protein engineering; kinetics and thermodynamics; materials science; manufacturing and biofabrication; and microsystems.

癌症工程学是一种跨学科方法,有望通过整合工程学和物理科学的创新领域来应对癌症的复杂性并加速变革性发现,重点关注癌症。我们为癌症工程的特点提供了一个概念框架,整合了 12 个领域:系统动力学;成像、辐射和光谱学;机器人和控制;固体力学;流体力学;化学和纳米材料;数学和模拟;细胞和蛋白质工程;动力学和热力学;材料科学;制造和生物制造;以及微系统。
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引用次数: 0
Engineering focusing on cancer 以癌症为重点的工程学
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-06-06 DOI: 10.1016/j.ccell.2024.04.013
Kayvan R. Keshari, Daniel A. Heller, Rostislav Boltyanskiy, Hedvig Hricak, Thomas Magaldi, Michael Overholtzer

While cancer research and care have benefited from revolutionary advances in the ability to manipulate and study living systems, the field is limited by a lack of synergy to leverage the power of engineering approaches. Cancer engineering is an emerging subfield of biomedical engineering that unifies engineering and cancer biology to better understand, diagnose, and treat cancer. We highlight cancer engineering’s unique challenges, the importance of creating dedicated centers and departments that enable translational collaboration, and educational approaches to arm a new generation of scientists with engineering expertise and a fundamental understanding of cancer biology to transform clinical cancer care.

虽然癌症研究和治疗得益于操纵和研究生命系统能力的革命性进步,但该领域却因缺乏协同作用而受到限制,无法充分利用工程方法的力量。癌症工程学是生物医学工程学的一个新兴子领域,它将工程学与癌症生物学结合起来,以更好地理解、诊断和治疗癌症。我们强调了癌症工程的独特挑战、建立专门中心和部门以促进转化合作的重要性,以及用工程专业知识和对癌症生物学的基本理解武装新一代科学家的教育方法,以改变临床癌症治疗。
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引用次数: 0
Identification of specific PP2A complexes involved in human cell transformation 鉴定参与人类细胞转化的特定 PP2A 复合物
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-30 DOI: 10.1016/j.ccell.2024.05.010
Wen Chen, Richard Possemato, K. Thirza Campbell, Courtney A. Plattner, David C. Pallas, William C. Hahn
No Abstract
无摘要
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引用次数: 0
Neural deception: Breast cancer co-opts neuronal mechanisms to evade the immune system 神经欺骗:乳腺癌利用神经元机制躲避免疫系统的攻击
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-30 DOI: 10.1016/j.ccell.2024.05.007
Nikolas Layer, Lukas Bunse, Varun Venkataramani

Cellular mechanisms mediating immunotherapy resistances are incompletely understood. In this issue, Li et al. reveal how breast cancer hijacks neuronal mechanisms of neuroprotection to shield itself from the immune system. Secretion of N-acetylaspartate impairs immune synapse formation in both neuroinflammation and breast cancer models, paving the way for novel therapeutic approaches.

介导免疫疗法抵抗的细胞机制尚不完全清楚。在本期杂志中,Li 等人揭示了乳腺癌如何劫持神经元的神经保护机制,使自己免受免疫系统的攻击。在神经炎症和乳腺癌模型中,N-乙酰天冬氨酸的分泌都会损害免疫突触的形成,从而为新型治疗方法铺平道路。
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引用次数: 0
Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite 肿瘤细胞通过富含中枢神经系统的代谢物损害免疫突触的形成
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-30 DOI: 10.1016/j.ccell.2024.05.006
Yihong Li, Min Huang, Minger Wang, Yi Wang, Peng Deng, Chunni Li, Jingying Huang, Hui Chen, Zhihao Wei, Qian Ouyang, Jinghua Zhao, Yiwen Lu, Shicheng Su

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.

肿瘤采用各种策略逃避免疫监视。中枢神经系统(CNS)具有抑制免疫反应的多种特征。肿瘤和中枢神经系统是否共享类似的免疫抑制程序尚不明确。在这里,我们分析了接受曲妥珠单抗和抗PD-L1抗体治疗的HER2+乳腺癌患者肿瘤的多组学数据,发现中枢神经系统富含的N-乙酰转移酶8样(NAT8L)及其代谢产物N-乙酰天冬氨酸(NAA)在耐药肿瘤中过度表达。在中枢神经系统中,NAA 在脑部炎症期间释放。NAT8L 通过 NAA 抑制自然杀伤(NK)细胞和 CD8+ T 细胞的细胞毒性,从而减轻脑部炎症并损害抗肿瘤免疫。NAA通过促进PCAF诱导的片层蛋白A-K542乙酰化破坏免疫突触的形成,从而抑制片层蛋白A和SUN2之间的整合,并损害裂解颗粒的极化。我们发现肿瘤细胞模仿中枢神经系统的抗炎机制来逃避抗肿瘤免疫,而NAT8L是提高抗癌药物疗效的潜在靶点。
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引用次数: 0
Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer 嗅神经母细胞瘤模拟小细胞肺癌的分子异质性和细胞系轨迹
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-23 DOI: 10.1016/j.ccell.2024.05.003
John B. Finlay, Abbie S. Ireland, Sarah B. Hawgood, Tony Reyes, Tiffany Ko, Rachelle R. Olsen, Ralph Abi Hachem, David W. Jang, Diana Bell, Joseph M. Chan, Bradley J. Goldstein, Trudy G. Oliver

The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity—evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.

嗅上皮细胞从基底干细胞中进行神经元再生,容易患上嗅神经母细胞瘤(ONB),这是一种起源不明的罕见肿瘤。通过改变 Rb1/Trp53/Myc (RPM),我们建立了一种基因工程小鼠模型,该模型为高级别转移性嗅神经母细胞瘤,表现出 NEUROD1+ 未成熟神经元表型。我们证明了球状基底细胞(GBC)是ONB的一个允许起源细胞,而且ONB表现出细胞命运异质性,模拟了正常的GBC发育轨迹。RPM ONB 中 ASCL1 的缺失会导致非神经元组织病理学的出现,包括 POU2F3+ 微绒毛样状态。与小细胞肺癌(SCLC)相似,小鼠和人类ONB也表现出相互排斥的NEUROD1和POU2F3样状态、免疫冷肿瘤微环境、瘤内细胞命运异质性(包括神经元和非神经元系)以及细胞命运可塑性--这些都可以通过基于条形码的系谱追踪和单细胞转录组学得到证实。总之,我们的研究结果凸显了ONB和神经内分泌肿瘤之间的相似性,对ONB的分类和治疗具有重要意义。
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引用次数: 0
Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators 神经内分泌癌的分子亚型:基于五种转录调节因子的跨组织分类框架
IF 50.3 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-23 DOI: 10.1016/j.ccell.2024.05.002
Zhanyu Wang, Chengming Liu, Sufei Zheng, Yuxin Yao, Sihui Wang, Xinfeng Wang, Enzhi Yin, Qingpeng Zeng, Chaoqi Zhang, Guochao Zhang, Wei Tang, Bo Zheng, Liyan Xue, Zhen Wang, Xiaoli Feng, Yan Wang, Jianming Ying, Qi Xue, Nan Sun, Jie He

Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.

神经内分泌癌(NEC)是一种致死率极高的恶性肿瘤,几乎可发生在任何解剖部位。由于神经内分泌癌非常罕见,且组织间和组织内异质性显著,因此其特征描述受到阻碍。在这里,我们通过对源自31种不同组织的1000多种NECs进行综合分析,揭示了它们与组织无关的趋同性,并进一步揭示了由不同转录调节因子驱动的分子分化。因此,泛组织 NECs 被划分为由 ASCL1、NEUROD1、HNF4A、POU2F3 和 YAP1 定义的五种内在亚型。本文描绘了这些亚型的综合特征,突出了亚型特异性转录程序、基因组改变、进化轨迹、治疗弱点和临床病理表现。值得注意的是,新发现的以HNF4A为主的亚型-H表现出胃肠道样特征、野生型RB1、独特的神经内分泌分化、化疗反应差和普遍的大细胞形态。统一分类范式的提出阐明了 NEC 异质性的转录基础,并弥合了不同系谱和细胞形态变异之间的差距,其中亚型的流行程度取决于环境,而环境是其表型差异的基础。
{"title":"Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators","authors":"Zhanyu Wang, Chengming Liu, Sufei Zheng, Yuxin Yao, Sihui Wang, Xinfeng Wang, Enzhi Yin, Qingpeng Zeng, Chaoqi Zhang, Guochao Zhang, Wei Tang, Bo Zheng, Liyan Xue, Zhen Wang, Xiaoli Feng, Yan Wang, Jianming Ying, Qi Xue, Nan Sun, Jie He","doi":"10.1016/j.ccell.2024.05.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.002","url":null,"abstract":"<p>Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by <em>ASCL1</em>, <em>NEUROD1</em>, <em>HNF4A</em>, <em>POU2F3</em>, and <em>YAP1</em>. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered <em>HNF4A</em>-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type <em>RB1</em>, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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Cancer Cell
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