Pub Date : 2024-06-10DOI: 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.
{"title":"Let it be: Preserving tumor-draining lymph nodes in the era of immuno-oncology","authors":"Robert Saddawi-Konefka, Shiruyeh Schokrpur, J. Silvio Gutkind","doi":"10.1016/j.ccell.2024.05.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.015","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299221","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}
Pub Date : 2024-06-10Epub Date: 2024-05-30DOI: 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
{"title":"Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice.","authors":"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","doi":"10.1016/j.ccell.2024.05.009","DOIUrl":"10.1016/j.ccell.2024.05.009","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183921","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}
Pub Date : 2024-06-06DOI: 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.
{"title":"RNA vaccines for cancer: Principles to practice","authors":"Pablo Guasp, Charlotte Reiche, Zachary Sethna, Vinod P. Balachandran","doi":"10.1016/j.ccell.2024.05.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.005","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265022","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}
Pub Date : 2024-06-06DOI: 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.
{"title":"Engineering cancer’s end: An interdisciplinary approach to confront the complexities of cancer","authors":"Elsa R. Flores, W. Gregory Sawyer","doi":"10.1016/j.ccell.2024.05.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.017","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265035","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}
Pub Date : 2024-06-06DOI: 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.
{"title":"Engineering focusing on cancer","authors":"Kayvan R. Keshari, Daniel A. Heller, Rostislav Boltyanskiy, Hedvig Hricak, Thomas Magaldi, Michael Overholtzer","doi":"10.1016/j.ccell.2024.04.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.04.013","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141265092","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}
Pub Date : 2024-05-30DOI: 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
{"title":"Identification of specific PP2A complexes involved in human cell transformation","authors":"Wen Chen, Richard Possemato, K. Thirza Campbell, Courtney A. Plattner, David C. Pallas, William C. Hahn","doi":"10.1016/j.ccell.2024.05.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.010","url":null,"abstract":"No Abstract","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177941","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}
Pub Date : 2024-05-30DOI: 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.
{"title":"Neural deception: Breast cancer co-opts neuronal mechanisms to evade the immune system","authors":"Nikolas Layer, Lukas Bunse, Varun Venkataramani","doi":"10.1016/j.ccell.2024.05.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.007","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177853","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}
Pub Date : 2024-05-30DOI: 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。
{"title":"Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite","authors":"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","doi":"10.1016/j.ccell.2024.05.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.006","url":null,"abstract":"<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":50.3,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177884","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}
Pub Date : 2024-05-23DOI: 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.
{"title":"Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer","authors":"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","doi":"10.1016/j.ccell.2024.05.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.05.003","url":null,"abstract":"<p>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 <em>Rb1/Trp53/Myc</em> (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1<sup>+</sup> 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<sup>+</sup> 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.</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":"141085727","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}
Pub Date : 2024-05-23DOI: 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 ASCL1, NEUROD1, 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}