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Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy 用泊纳替尼和阿西米尼联合疗法克服临床BCR-ABL1复合突变耐药性
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.004
Christopher A. Eide, Diana Brewer, Tao Xie, Anna Reister Schultz, Samantha L. Savage, Serena Muratcioglu, Noah Merz, Richard D. Press, Thomas O’Hare, Thomas Jacob, Tania Q. Vu, Cristina E. Tognon, Tara A. Macey, John Kuriyan, Charalampos G. Kalodimos, Brian J. Druker
No Abstract
无摘要
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引用次数: 0
The KRAS mutational spectrum and its clinical implications in pancreatic cancer 胰腺癌 KRAS 基因突变谱及其临床意义
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.001
Luigi Perelli, Giannicola Genovese, Giulio F. Draetta

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

在本期《癌细胞》(Cancer Cell)杂志上,McIntyre 等人发现 KRAS 原癌基因的特定突变会影响胰腺导管腺癌(PDAC)的临床进展。重要的是,他们发现KRASG12R突变在早期PDAC中富集,其特点是分子程序被明显激活。
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引用次数: 0
Precision oncology across the ages: Impact on children, adolescents, and young adults 跨年龄段的精准肿瘤学:对儿童、青少年和年轻人的影响
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.010
Vivek Subbiah, Razelle Kurzrock

Precision oncology endeavors to tailor therapies based on individual patient and tumor characteristics. This rapidly evolving field has transformed cancer treatment across all age groups. In this commentary, we review the application of precision oncology across different age groups, specifically in children, adolescents, and young adults, and emphasize that precision medicine is age and tissue agnostic.

精准肿瘤学致力于根据患者和肿瘤的个体特征量身定制治疗方案。这一快速发展的领域已经改变了所有年龄组的癌症治疗。在这篇评论中,我们回顾了精准肿瘤学在不同年龄段的应用,特别是在儿童、青少年和年轻成人中的应用,并强调精准医学与年龄和组织无关。
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引用次数: 0
Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors 癌细胞状态:人类肿瘤单细胞 RNA 测序十年的启示
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.005
Itay Tirosh, Mario L. Suva

Human tumors are intricate ecosystems composed of diverse genetic clones and malignant cell states that evolve in a complex tumor micro-environment. Single-cell RNA-sequencing (scRNA-seq) provides a compelling strategy to dissect this intricate biology and has enabled a revolution in our ability to understand tumor biology over the last ten years. Here we reflect on this first decade of scRNA-seq in human tumors and highlight some of the powerful insights gleaned from these studies. We first focus on computational approaches for robustly defining cancer cell states and their diversity and highlight some of the most common patterns of gene expression intra-tumor heterogeneity (eITH) observed across cancer types. We then discuss ambiguities in the field in defining and naming such eITH programs. Finally, we highlight critical developments that will facilitate future research and the broader implementation of these technologies in clinical settings.

人类肿瘤是一个错综复杂的生态系统,由不同的基因克隆和恶性细胞状态组成,在复杂的肿瘤微环境中不断演变。单细胞 RNA 测序(scRNA-seq)提供了一种令人信服的策略来剖析这种错综复杂的生物学特性,并在过去十年中使我们了解肿瘤生物学的能力发生了革命性的变化。在此,我们回顾了人类肿瘤 scRNA-seq 研究的第一个十年,并重点介绍了从这些研究中获得的一些重要启示。首先,我们将重点放在稳健定义癌细胞状态及其多样性的计算方法上,并强调在不同癌症类型中观察到的一些最常见的基因表达肿瘤内异质性(eITH)模式。然后,我们讨论了该领域在定义和命名此类 eITH 方案时存在的模糊之处。最后,我们强调了将促进未来研究和在临床环境中更广泛实施这些技术的关键发展。
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引用次数: 0
PD-1 blockade is a promising therapeutic addition to neoadjuvant chemoradiation in locally advanced rectal cancer 在局部晚期直肠癌的新辅助化疗中,PD-1 阻断剂是一种很有前景的辅助疗法
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.003
Ashwin Somasundaram, Hanna K. Sanoff

Neoadjuvant chemoradiotherapy has been a mainstay of the treatment of locally advanced rectal cancer. Programmed cell death protein 1 (PD-1) blockade therapy has demonstrated efficacy in combination with radiation. In this issue, Xiao et al. demonstrate promising efficacy with the addition of PD-1 blockade to neoadjuvant therapy for mismatch-repair proficient rectal cancer.

新辅助化放疗一直是治疗局部晚期直肠癌的主要方法。程序性细胞死亡蛋白1(PD-1)阻断疗法与放疗联合使用已显示出疗效。在本期杂志中,Xiao等人证明了在错配修复熟练的直肠癌新辅助治疗中加入PD-1阻断剂具有良好的疗效。
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引用次数: 0
Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer 人类胰腺癌中特定 KRAS 突变体的不同临床结果和生物学特征
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.002
Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

胰腺导管腺癌(PDAC)中的 KRAS 突变被认为具有不同的致癌性,但其对人类患者的影响尚未得到深入探讨。我们对接受手术切除的 1,360 例连续的 PDAC 患者进行了研究,发现 KRASG12R 突变富集于早期(I 期)疾病,这并不是因为肿瘤较小,而是因为结节阴性增加。与KRASG12D相比,KRASG12R肿瘤的远处复发率降低,生存率提高。为了了解其生物学基础,我们对20名患者进行了空间谱分析,并对100个肿瘤进行了大量RNA测序,发现KRASG12D肿瘤的致癌信号转导和上皮-间质转化(EMT)增强,而KRASG12R肿瘤的核因子κB(NF-κB)信号转导增强。对小鼠 KrasG12R PDAC 器官组织的正交研究显示,在正位模型中,迁移减少,存活率提高。因此,PDAC 中的 KRAS 改变与不同的表现形式、临床结果和生物学行为有关,突显了突变分析的预后价值以及阐明突变特异性 PDAC 生物学的重要性。
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引用次数: 0
Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells 抗-PD-1和抗-CTLA-4疗法联合疗法产生的克隆反应波包括祖细胞耗竭的CD8+T细胞
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.007
Kevin Wang, Paulina Coutifaris, David Brocks, Guanning Wang, Tarek Azar, Sabrina Solis, Ajeya Nandi, Shaneaka Anderson, Nicholas Han, Sasikanth Manne, Evgeny Kiner, Chirag Sachar, Minke Lucas, Sangeeth George, Patrick K. Yan, Melanie W. Kier, Amy I. Laughlin, Shawn Kothari, Josephine Giles, Divij Mathew, Alexander C. Huang

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

抗PD-1和抗CTLA-4抗体联合检查点阻断疗法在黑色素瘤中显示出了良好的疗效。然而,人类的潜在机制仍不清楚。在这里,我们对36名接受抗PD-1、抗CTLA-4或联合疗法治疗的IV期黑色素瘤患者进行了成对单细胞RNA和T细胞受体(TCR)跨时间测序。我们开发了 Cyclone 算法来跟踪克隆的时间动态和潜在的细胞状态。检查点阻断诱导了一波波克隆 T 细胞反应,这些反应在不同的时间点达到峰值。与单药疗法相比,联合疗法能在6周和9周时产生更大规模的克隆反应,包括黑色素瘤特异性CD8+ T细胞和衰竭CD8+ T细胞(TEX)克隆。对TEX的集中分析表明,抗CTLA-4能诱导祖细胞TEX的强力扩增和增殖,它与抗PD-1协同作用,在联合疗法中为TEX注入新的活力。这些新一代免疫分析方法可以指导新型联合疗法的药物选择、疗程安排和剂量。
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引用次数: 0
Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers 长效 mRNA 编码的白细胞介素-2 可恢复 MHC I 类缺陷癌症患者的 CD8+ T 细胞新抗原免疫力
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.010
No Abstract
无摘要
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引用次数: 0
CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis 产生 CCL19 的成纤维细胞可促进三级淋巴结构的形成,增强结直肠癌肝转移中的抗肿瘤 IgG 反应
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.006

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS− tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS− tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.

三级淋巴结构(TLS)与肿瘤免疫力增强有关。然而,它们在结直肠癌肝转移(CRLM)中的形成和功能仍不清楚。在这里,我们揭示了肿瘤内和肿瘤周围成熟的 TLS(TLS+)比 TLS- 肿瘤更能改善临床预后。利用单细胞-RNA 测序和空间增强分辨组学测序(Stereo-seq),我们发现TLS+肿瘤富含IgG+浆细胞(PCs),而TLS-肿瘤则以IgA+ PCs为特征。通过在体外生成 TLS 相关 PC 衍生的单克隆抗体,我们发现 TLS-PCs 会分泌肿瘤靶向抗体。作为概念验证,我们在人源化小鼠结直肠癌模型中证明了 TLS-PC-mAb6 抗体的抗肿瘤活性。我们发现成纤维细胞系分泌的 CCL19 可促进淋巴细胞向 TLS 转移。CCL19 治疗可促进小鼠 TLS 的新生并阻止肿瘤生长。我们的数据揭示了CCL19+成纤维细胞在TLS形成中的核心作用,这反过来又产生了限制CRLM的治疗性抗体。
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引用次数: 0
Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer 开发前列腺癌 ERG 基因融合产物的拟肽抑制剂
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.009
No Abstract
无摘要
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引用次数: 0
期刊
Cancer Cell
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