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Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma. 胸膜间皮瘤肿瘤微环境梯度的单细胞视图。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-0017
Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja M Flores, Robert P Sebra, Amir Horowitz, Thomas U Marron, Anna Tocheva, Andrea Wolf, Alexander M Tsankov

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Across cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, and cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A:HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases. Significance: This manuscript presents the first single-cell RNA sequencing atlas of PM tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM.

免疫疗法在胸膜间皮瘤(PM)中显示出了巨大的前景,但大多数患者仍未获得明显的临床反应,这凸显了加深了解肿瘤微环境(TME)的重要性。在这里,我们利用高通量单细胞RNA测序技术从新识别了54种表达程序,并构建了胸膜间皮瘤TME的综合细胞目录。我们发现了四种与不良疾病预后相关的癌症内在程序,以及一种新型胎儿样内皮细胞群,这种细胞群可能会对血管内皮生长因子信号做出反应并促进血管生成。在整个细胞分区中,我们观察到与癌症内在肉瘤特征相关的 TME 存在巨大差异,包括胎儿样内皮细胞、CXCL9+ 巨噬细胞、细胞毒性 T 细胞、衰竭 T 细胞和调节性 T 细胞的富集。最后,我们通过计算和实验表明,NK 和肿瘤细胞之间的 NKG2A-HLA-E 相互作用代表了 PM 重要的新治疗轴,尤其是对于上皮样病例。
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引用次数: 0
Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research. 精准肿瘤学和癌症转化研究中的高度复用组织成像。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1165
Alina Bollhagen, Bernd Bodenmiller

Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.

精准肿瘤学根据患者的分子和健康数据制定治疗策略。尽管目前的诊断方法具有重要的临床价值,但苏木精和伊红形态学、免疫组化和基因组测序只能提供不完整的特征描述。相比之下,高度复用的组织成像技术能以单细胞分辨率对数十种标记物进行空间分析,从而对复杂的肿瘤生态系统进行分析;因此,它有可能促进我们对癌症生物学的了解,并支持药物开发、生物标记物发现和患者分层。我们介绍了现有的高度复用成像模式,讨论了它们在临床应用中的优缺点,以及将这些模式应用于临床实践的潜在途径。意义重大:本综述就如何将患者样本的高分辨率多重组织成像整合到临床工作流程中提供了指导。它系统地比较了现有技术和新兴技术,并概述了在精准肿瘤学领域的潜在应用,从而将不断发展的癌症研究与高度多重组织成像在常规临床实践中的实际应用可能性联系起来。
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引用次数: 0
A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. 经典上皮状态促使胰腺癌对 KRAS 抑制产生急性耐药性。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0740
Anupriya Singhal, Hannah C Styers, Jonathan Rub, Zhuxuan Li, Stefan R Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela

Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials, but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage tracing uncovers that these enriched classical PDAC cells are a reservoir for disease relapse. Genetic or chemotherapy-mediated ablation of the classical cell state is synergistic with KRAS inhibition, providing a preclinical proof of concept for this therapeutic strategy. Our findings motivate combining classical state-directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer. Significance: KRAS inhibitors hold promise in pancreatic cancer, but responses are limited by acquired resistance. We find that a classical epithelial cancer cell state is acutely resistant to KRAS inhibition and serves as a reservoir for disease relapse. Targeting the classical state alongside KRAS inhibition deepens responses, revealing a potent therapeutic strategy. See related commentary by Marasco and Misale, p. 2018.

胰腺导管腺癌(PDAC)瘤内异质性的特点是基底细胞和典型上皮癌细胞状态之间的平衡,基底细胞占优势与化疗耐药性和预后不良有关。靶向致癌 KRAS(胰腺癌的主要驱动因素)在临床试验中显示出早期前景,但疗效受到获得性耐药性的限制。通过使用基因工程小鼠模型和患者衍生异种移植,我们发现基础 PDAC 细胞对 KRAS 抑制剂高度敏感。利用荧光和生物发光报告系统,我们纵向追踪了体内的细胞状态动态,发现了 KRAS 抑制剂诱导的经典状态的快速富集。系谱追踪发现,这些富集的经典 PDAC 细胞是疾病复发的储库。经典细胞态的基因消减与 KRAS 抑制具有协同作用,为这种治疗策略提供了临床前概念验证。我们的研究结果促使我们将经典细胞态定向疗法与 KRAS 抑制剂相结合,以加深胰腺癌患者的反应并对抗耐药性。
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引用次数: 0
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma. 铜驱动新陈代谢状态的重塑和透明细胞肾细胞癌的进展。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-31 DOI: 10.1158/2159-8290.CD-24-0187
Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska

Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.

铜(Cu)是细胞色素 c 氧化酶(CuCOX)的辅助因子,是有氧线粒体呼吸不可或缺的物质。这项研究发现,晚期透明细胞肾细胞癌(ccRCC)会积累铜,并将其分配给CuCOX。我们采用了一系列正交方法,包括代谢组学、脂质组学、同位素标记的葡萄糖和谷氨酰胺通量分析以及肿瘤样本、细胞系、异种移植和 PDX 模型的转录组学,并结合基因和药物干预,探讨了 Cu 在 ccRCC 中的作用。Cu水平升高会刺激CuCOX的生物生成,提供生物能和生物合成益处,从而促进肿瘤生长。葡萄糖依赖性谷胱甘肽的产生补充了这一作用,促进了解毒并减轻了 Cu-H2O2 的毒性。单细胞 RNA 测序(scRNA-seq)和空间转录组学揭示了 ccRCC 进展过程中氧化代谢增加、谷胱甘肽和铜代谢改变以及 HIF 活性降低。因此,铜推动了生物能、生物合成和氧化还原平衡的综合致癌重塑,助长了ccRCC的生长,而这可以成为新治疗方法的靶点。
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引用次数: 0
CTR-FAPI PET enables precision management of medullary thyroid carcinoma. CTR-FAPI PET 实现了甲状腺髓样癌的精准治疗。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-29 DOI: 10.1158/2159-8290.CD-24-0897
Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.

甲状腺髓样癌(MTC)只有通过切除所有转移灶才能治愈,但在目前的临床实践中,有29%-60%的患者无法对疾病进行定位。此前,我们开发了一种基于成纤维细胞活化蛋白抑制剂(FAPI)的共价靶向放射性配体(CTR),以提高检测灵敏度和准确性。在这项首创的临床试验中,我们对 50 名 MTC 患者进行了[68Ga]Ga-CTR-FAPI PET-CT 和[18F]FDG PET-CT 的头对头比较。主要终点是基于患者的检出率,[68Ga]Ga-CTR-FAPI的检出率高于[18F]FDG(98% 对 66%,P=0.0002)。检测率的提高归因于肿瘤摄取量的增加(SUVmax 11.71±9.16 vs. 2.55±1.73,p
{"title":"CTR-FAPI PET enables precision management of medullary thyroid carcinoma.","authors":"Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu","doi":"10.1158/2159-8290.CD-24-0897","DOIUrl":"10.1158/2159-8290.CD-24-0897","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521077","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
Cancer Prevalence across Vertebrates 脊椎动物的癌症发病率
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-24 DOI: 10.1158/2159-8290.cd-24-0573
Zachary T. Compton, Walker Mellon, Valerie K. Harris, Shawn Rupp, Diego Mallo, Stefania E. Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N. Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G. Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I. Li, Ashley Zehnder, Trevor A. Graham, Brigid V. Troan, Tara M. Harrison, Marc Tollis, Joshua D. Schiffman, C. Athena Aktipis, Lisa M. Abegglen, Carlo C. Maley, Amy M. Boddy
Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto’s paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (&lt;1.3%), the Rodrigues fruit bat (&lt;1.6%), the black-footed penguin (&lt;0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.
癌症在多细胞物种中普遍存在,但不同物种的癌症发病率有何差异?通过对横跨四足动物三个支系(两栖类、梭形类和哺乳类)的 292 个物种的 16,049 份尸检记录进行分析,我们发现肿瘤和恶性肿瘤的发病率随着成体质量(与佩托悖论相反)和体细胞突变率的增加而增加,但随着妊娠时间的延长而减少。只有当我们控制了妊娠时间后,成体质量与恶性肿瘤发病率之间的关系才变得明显。癌症易感性的进化似乎经历了突然的转变,然后是稳定的选择。肿瘤发病率的异常值包括普通鼠海豚(&lt;1.3%)、罗德里格斯果蝠(&lt;1.6%)、黑脚企鹅(&lt;0.4%)、雪貂(63%)和负鼠(35%)。发现某些物种癌症发病率特别高或特别低的原因,可能有助于更好地了解癌症综合征,并制定新的癌症管理和预防策略。意义重大:进化发现了各种物种抑制癌症的机制。通过分析兽医尸检记录,我们可以确定癌症发病率特别高或特别低的物种。发现癌症易感性和抵抗力的机制可能有助于改善癌症预防和解释癌症综合症。
{"title":"Cancer Prevalence across Vertebrates","authors":"Zachary T. Compton, Walker Mellon, Valerie K. Harris, Shawn Rupp, Diego Mallo, Stefania E. Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N. Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G. Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I. Li, Ashley Zehnder, Trevor A. Graham, Brigid V. Troan, Tara M. Harrison, Marc Tollis, Joshua D. Schiffman, C. Athena Aktipis, Lisa M. Abegglen, Carlo C. Maley, Amy M. Boddy","doi":"10.1158/2159-8290.cd-24-0573","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0573","url":null,"abstract":"Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto’s paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (&amp;lt;1.3%), the Rodrigues fruit bat (&amp;lt;1.6%), the black-footed penguin (&amp;lt;0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489809","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
The Journey of Antibody-Drug Conjugates: Lessons Learned from 40 Years of Development. 抗体药物共轭物的发展历程:从 40 年的发展中汲取的经验教训。
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-23 DOI: 10.1158/2159-8290.cd-24-0708
Raffaele Colombo,Paolo Tarantino,Jamie R Rich,Patricia M LoRusso,Elisabeth G E de Vries
Antibody-drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.
抗体药物共轭物(ADC)是肿瘤学领域发展最迅速的治疗方式之一,目前已有 11 种 ADC 获得美国食品及药物管理局(FDA)批准,210 多种 ADC 正在接受临床试验。ADC 临床开发历时 40 余年,加深了我们对该类疗法多方面作用机制的了解。在本文中,我们将讨论有关 ADC 的毒性、疗效、稳定性、分布和转归的重要见解。此外,我们还重点介绍了在临床优化、合理测序策略的开发以及预测性生物标记物的鉴定方面所面临的挑战。意义重大:ADCs 的开发和利用使多种癌症类型的预后得到了相关改善。与此同时,ADCs 在肿瘤学领域的兴起也带来了一些挑战,包括对其活性的预测、按顺序使用以及最大限度地减少其副作用,而这些副作用往往与它们所携带的细胞毒性分子的副作用相似。在这篇综述中,我们回顾了 ADC 领域 40 年的发展历程,并深入探讨了这些复杂疗法的作用机制,以及该领域迄今为止取得的众多成就和失败背后的原因。
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引用次数: 0
The Evolutionary Forest of Pancreatic Cancer 胰腺癌的进化森林
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-08 DOI: 10.1158/2159-8290.cd-23-1541
Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue
The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal or mixed polyclonal/monoclonal metastases were identified across the cohort highlighting multiple forms of inter-tumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms.
胰腺导管腺癌(PDAC)的基因组特征已经得到了很好的描述,但这些特征发生的进化背景仍有待探索。我们研究了 91 例 PDAC 的基因组图谱、系统发育和克隆组成与临床病理特征的关系。在驱动突变的数量或每个突变发生的进化时间上没有差异。截干密度高(这是产生每个 PDAC 的系谱中体细胞突变积累的指标)与总生存率较低有显著相关性。在整个组群中发现了多克隆、单克隆或多克隆/单克隆混合转移瘤,突显了多种形式的肿瘤间异质性。晚期和经过治疗的PDAC发生多克隆转移的几率更高,而少转移的PDAC驱动基因改变较少,等位基因丢失的比例较低,发生单克隆转移的可能性增加。总之,我们的研究结果揭示了PDAC基因组动态性质的新见解,超越了既有的遗传范式。
{"title":"The Evolutionary Forest of Pancreatic Cancer","authors":"Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue","doi":"10.1158/2159-8290.cd-23-1541","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1541","url":null,"abstract":"The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal or mixed polyclonal/monoclonal metastases were identified across the cohort highlighting multiple forms of inter-tumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":28.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385205","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
Glioblastoma-cortical organoids recapitulate cell state heterogeneity and intercellular transfer. 胶质母细胞瘤皮质器官再现细胞状态异质性和细胞间转移
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-07 DOI: 10.1158/2159-8290.CD-23-1336
Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suva

Glioblastoma is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. Here, we model this ecosystem by growing glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA-seq analysis suggests that, compared to matched gliomasphere models, glioblastoma cortical organoids (GCO) more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of glioblastoma transcripts and GFP proteins to non-malignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased towards defined glioblastoma cell states and astroglia cell types. These results extend previous glioblastoma-organoid modeling efforts and suggest widespread intercellular transfer in the glioblastoma neuroglial microenvironment.

胶质母细胞瘤的特征是神经胶质细胞微环境中功能整合的异质性恶性细胞。在这里,我们通过将胶质母细胞瘤培养到长期培养的人皮质器官组织中来模拟这一生态系统,该器官组织包含大脑皮质中的主要神经胶质细胞类型。单细胞RNA-seq分析表明,与匹配的胶质母球模型相比,胶质母细胞瘤皮质类器官(GCO)更忠实地再现了患者肿瘤中恶性细胞状态的多样性和表达程序。此外,我们还观察到胶质母细胞瘤转录本和 GFP 蛋白广泛转移到器官组织中的非恶性细胞。从机理上讲,这种转移涉及细胞外囊泡,并偏向于确定的胶质母细胞瘤细胞状态和星形胶质细胞类型。这些结果扩展了以前的胶质母细胞瘤-类器官建模工作,并表明胶质母细胞瘤神经胶质细胞微环境中存在广泛的细胞间转移。
{"title":"Glioblastoma-cortical organoids recapitulate cell state heterogeneity and intercellular transfer.","authors":"Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suva","doi":"10.1158/2159-8290.CD-23-1336","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-23-1336","url":null,"abstract":"<p><p>Glioblastoma is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. Here, we model this ecosystem by growing glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA-seq analysis suggests that, compared to matched gliomasphere models, glioblastoma cortical organoids (GCO) more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of glioblastoma transcripts and GFP proteins to non-malignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased towards defined glioblastoma cell states and astroglia cell types. These results extend previous glioblastoma-organoid modeling efforts and suggest widespread intercellular transfer in the glioblastoma neuroglial microenvironment.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380088","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
Can Ruxolitinib Crash TET2- and IDH2-Driven Clonal Hematopoiesis? Ruxolitinib能否抑制TET2-和IDH2-驱动的克隆性造血?
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/2159-8290.CD-24-1020
Elmira Khabusheva, Margaret A Goodell

In this issue, Waarts and colleagues developed an advanced ex vivo CRISPR screening platform to identify vulnerabilities in clonal hematopoiesis (CH). This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible path for preventing the development of malignancy. See related article by Waarts et al., p. 1860.

在本期杂志中,Waarts及其同事开发了一种先进的体外CRISPR筛选平台,用于识别克隆造血(CH)中的漏洞。这一独特的系统使作者能够确定 IDH2 和 TET2 CH 突变、组蛋白去甲基化酶和细胞因子信号转导改变之间的联系,从而通过 ruxolitinib 靶向消除 CH 克隆,为预防恶性肿瘤的发展提供了可能的途径。参见Waarts等人的相关文章,第1860页。
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引用次数: 0
期刊
Cancer discovery
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