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Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain 不同的肿瘤结构和微环境促进了乳腺癌在大脑中的转移
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.ccell.2024.08.015
Siting Gan, Danilo G. Macalinao, Sayyed Hamed Shahoei, Lin Tian, Xin Jin, Harihar Basnet, Catherine Bibby, James T. Muller, Pranita Atri, Evan Seffar, Walid Chatila, Ali Karacay, Pharto Chanda, Anna-Katerina Hadjantonakis, Nikolaus Schultz, Edi Brogi, Tejus A. Bale, Nelson S. Moss, Rajmohan Murali, Dana Pe’er, Joan Massagué

Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer’s disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.

脑转移是癌症的一种严重并发症,取决于扩散癌细胞的初期生存、微环境适应和生长。为了了解脑部定植的早期阶段,我们研究了两种常见的脑部复发来源--三阴性(TNBC)和HER2+(HER2BC)乳腺癌。通过使用小鼠模型和人体组织样本,我们发现这些肿瘤类型在大脑中的定植偏好于独特的肿瘤结构、基质界面和自分泌程序。TNBC 模型倾向于形成与星形胶质细胞和小胶质细胞弥散性接触的血管周围鞘。与此相反,HER2BC 模型倾向于在自主腱鞘蛋白 C 生成的驱动下形成紧凑的球体,将基质细胞分隔到外围。肿瘤微环境的单细胞转录组学显示,这些结构会唤起不同的阿尔茨海默病相关小胶质细胞(DAM)反应和GAS6受体AXL的参与。这两种脑定植模式的空间特征对于利用基质治疗脑转移具有重要意义。
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引用次数: 0
Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow 胶质母细胞瘤诱导颅骨骨髓中树突状 "混合 "中性粒细胞的招募和分化
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.ccell.2024.08.008
Meeki Lad, Angad S. Beniwal, Saket Jain, Poojan Shukla, Venina Kalistratova, Jangham Jung, Sumedh S. Shah, Garima Yagnik, Atul Saha, Ankita Sati, Husam Babikir, Alan T. Nguyen, Sabraj Gill, Jennifer Rios, Jacob S. Young, Austin Lui, Diana Salha, Aaron Diaz, Manish K. Aghi

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features—including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation—accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this “hybrid” dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils—which we identified in patient and murine glioblastomas—arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow—such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report—present therapeutic potential.

肿瘤相关中性粒细胞(TAN)对胶质母细胞瘤(GBM)生物学的影响仍未得到充分描述。我们在本文中展示了具有树突状特征的中性粒细胞--包括形态复杂性、抗原递呈基因表达以及处理外源肽和刺激主要组织相容性复合体(MHC)II依赖性T细胞活化的能力--在肿瘤内聚集并抑制体内肿瘤生长。对患者TAN scRNA-seq的轨迹分析发现,这种树突状细胞-中性粒细胞 "混合 "表型是一种有别于典型细胞毒性TAN的极化状态,它是从局部前体分化而来的。这些混合诱导的未成熟中性粒细胞--我们在患者和小鼠胶质母细胞瘤中发现了它们--不是从血液循环中产生,而是从局部颅骨骨髓中产生。通过标记颅骨瓣移植和靶向消融,我们确定了颅骨骨髓是抗肿瘤髓系抗原递呈细胞(APCs)的贡献者,其中包括能激发T细胞细胞毒性和记忆的TANs。因此,促进中性粒细胞从颅骨骨髓中排出的药物--如颅骨内AMD3100--具有治疗潜力。
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引用次数: 0
Assessing clonal changes in T cells over time following immunotherapy is a breeze with Cyclone 使用 Cyclone 可轻松评估免疫疗法后 T 细胞随时间发生的克隆变化
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.ccell.2024.08.014
Anthony R. Cillo, John M. Kirkwood

Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of Cancer Cell, Wang et al.1 report dynamics and transcriptional states of CD8+ T cell clones over time in patients treated with anti-PD-1, anti-CTLA-4, or a combination of the two. These findings have important implications for understanding and monitoring combination immunotherapy.

联合免疫疗法能改善转移性黑色素瘤的治疗效果,但其潜在机制仍不清楚。在本期《癌细胞》(Cancer Cell)杂志上,Wang等人1报告了接受抗PD-1、抗CTLA-4或两者联合治疗的患者CD8+T细胞克隆的动态和转录状态。这些发现对理解和监测联合免疫疗法具有重要意义。
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引用次数: 0
Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence 抗CSF-1R疗法的纤维化反应会加剧胶质母细胞瘤的复发
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.ccell.2024.08.012
Spencer S. Watson, Anoek Zomer, Nadine Fournier, Joao Lourenco, Manfredo Quadroni, Agnieszka Chryplewicz, Sina Nassiri, Pauline Aubel, Simona Avanthay, Davide Croci, Erik Abels, Marike L.D. Broekman, Douglas Hanahan, Jason T. Huse, Roy T. Daniel, Monika E. Hegi, Krisztian Homicsko, Giulia Cossu, Andreas F. Hottinger, Johanna A. Joyce

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

尽管进行了广泛的标准治疗,但目前胶质母细胞瘤的复发仍不可避免。在临床前研究中,一种通过抑制 CSF-1R 靶向肿瘤相关巨噬细胞和小胶质细胞的替代策略被发现可以使已形成的肿瘤消退,并显著提高总生存率。然而,在长期研究中,有 50% 的小鼠出现了复发,而且始终伴有纤维化疤痕。在不同的临床前模型和患者复发样本中,都观察到了多种抗胶质瘤疗法后的纤维化反应。对治疗后肿瘤微环境的多组学分析发现,纤维化区域是有利于肿瘤存活的龛位,可包裹存活的胶质瘤细胞、促进休眠并抑制免疫监视。纤维化治疗反应是由血管周围衍生的成纤维细胞样细胞通过转化生长因子β(TGF-β)信号和神经炎症激活介导的。同时,对这些通路的联合抑制可抑制治疗相关的纤维化,并在抗集落刺激因子-1受体(CSF-1R)疗法的临床前试验中显著提高存活率。
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引用次数: 0
Classifying cancer-associated fibroblasts—The good, the bad, and the target 癌症相关成纤维细胞的分类--好的、坏的和目标
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.ccell.2024.08.011
Lena Cords, Natalie de Souza, Bernd Bodenmiller

Cancer-associated fibroblasts (CAFs) are heterogeneous and ubiquitous stromal cells within the tumor microenvironment (TME). Numerous CAF types have been described, typically using single-cell technologies such as single-cell RNA sequencing. There is no general classification system for CAFs, hampering their study and therapeutic targeting. We propose a simple CAF classification system based on single-cell phenotypes and spatial locations of CAFs in multiple cancer types, assess how our scheme fits within current knowledge, and invite the CAF research community to further refine it.

癌症相关成纤维细胞(CAFs)是肿瘤微环境(TME)中异质性的、无处不在的基质细胞。人们通常利用单细胞技术(如单细胞 RNA 测序)描述了许多 CAF 类型。目前还没有CAF的通用分类系统,这阻碍了对它们的研究和靶向治疗。我们根据多种癌症类型中 CAF 的单细胞表型和空间位置提出了一个简单的 CAF 分类系统,评估了我们的方案与现有知识的契合程度,并邀请 CAF 研究界进一步完善该系统。
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引用次数: 0
Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer 基于循环肿瘤 DNA 的晚期非小细胞肺癌化疗加 PD-1 抑制剂分层策略
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.ccell.2024.08.013
Jiachen Xu, Rui Wan, Yiran Cai, Shangli Cai, Lin Wu, Baolan Li, Jianchun Duan, Ying Cheng, Xiaoling Li, Xicheng Wang, Liang Han, Xiaohong Wu, Yun Fan, Yan Yu, Dongqing Lv, Jianhua Shi, Jianjin Huang, Shaozhang Zhou, Baohui Han, Guogui Sun, Jie Wang

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

晚期非小细胞肺癌(NSCLC)化疗加 PD-1 抑制剂的分层策略需求量很大。我们对 CHOICE-01 3 期研究中 460 例患者在不同时间点的循环肿瘤 DNA(ctDNA)标本进行了基于高通量面板的深度新一代测序和低通滤波全基因组测序。我们确定了化疗加 PD-1 抑制剂的预测标志物,包括 ctDNA 状态和基因组特征,如基于血液的肿瘤突变负荷、肿瘤内异质性和染色体不稳定性。此外,我们还建立了一种基于ctDNA的综合分层策略--基于血液的基因组免疫亚型(bGIS)方案,以区分哪些患者可从一线化疗加用PD-1抑制剂中获益。此外,我们还展示了ctDNA动态监测的潜在应用。总之,我们提出了一种基于ctDNA分层策略的潜在治疗算法,为晚期NSCLC患者的免疫化疗个体化管理提供了启示。
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引用次数: 0
Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma. 综合单细胞分析揭示了转化型滤泡淋巴瘤中恶性 B 细胞和肿瘤微环境的共同演化。
IF 48.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-09 Epub Date: 2024-08-15 DOI: 10.1016/j.ccell.2024.07.012
Clémentine Sarkozy, Shaocheng Wu, Katsuyoshi Takata, Tomohiro Aoki, Susana B Neriah, Katy Milne, Talia Goodyear, Celia Strong, Tashi Rastogi, Laura K Hilton, Daniel Lai, Laurie H Sehn, Pedro Farinha, Brad H Nelson, Andrew Weng, Marco Marra, David W Scott, Jeffrey W Craig, Christian Steidl, Andrew Roth
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引用次数: 0
Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma 单细胞的综合电生理和基因组图谱揭示了人类胶质瘤中的尖峰肿瘤细胞
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.ccell.2024.08.009
Rachel N. Curry, Qianqian Ma, Malcolm F. McDonald, Yeunjung Ko, Snigdha Srivastava, Pey-Shyuan Chin, Peihao He, Brittney Lozzi, Prazwal Athukuri, Junzhan Jing, Su Wang, Arif O. Harmanci, Benjamin Arenkiel, Xiaolong Jiang, Benjamin Deneen, Ganesh Rao, Akdes Serin Harmanci

Prior studies have described the complex interplay that exists between glioma cells and neurons; however, the electrophysiological properties endogenous to glioma cells remain obscure. To address this, we employed Patch-sequencing (Patch-seq) on human glioma specimens and found that one-third of patched cells in IDH mutant (IDHmut) tumors demonstrate properties of both neurons and glia. To define these hybrid cells (HCs), which fire single, short action potentials, and discern if they are of tumoral origin, we developed the single cell rule association mining (SCRAM) computational tool to annotate each cell individually. SCRAM revealed that HCs possess select features of GABAergic neurons and oligodendrocyte precursor cells, and include both tumor and non-tumor cells. These studies characterize the combined electrophysiological and molecular properties of human glioma cells and describe a cell type in human glioma with unique electrophysiological and transcriptomic properties that may also exist in the non-tumor brain.

先前的研究已经描述了胶质瘤细胞和神经元之间存在的复杂相互作用;然而,胶质瘤细胞的内源性电生理特性仍然不明显。为了解决这个问题,我们在人类胶质瘤标本上采用了补丁测序(Patch-sequencing,Patch-seq)技术,发现IDH突变(IDHmut)肿瘤中有三分之一的补丁细胞同时具有神经元和胶质细胞的特性。为了定义这些能发出单个短动作电位的混合细胞(HCs),并确定它们是否源于肿瘤,我们开发了单细胞规则关联挖掘(SCRAM)计算工具,对每个细胞进行单独注释。SCRAM 发现,HCs 具有 GABA 能神经元和少突胶质细胞前体细胞的特征,包括肿瘤细胞和非肿瘤细胞。这些研究描述了人类胶质瘤细胞的综合电生理学和分子特性,并描述了人类胶质瘤中一种具有独特电生理学和转录组学特性的细胞类型,这种细胞类型可能也存在于非肿瘤大脑中。
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引用次数: 0
GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant GABA能神经元谱系的发展决定了弥漫性半球胶质瘤、H3G34突变体的临床作用靶点
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-03 DOI: 10.1016/j.ccell.2024.08.006
Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca F. Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia A. Hack, Michael A. Quezada, Valeria Molinari, McKenzie L. Shaw, Marta Perez-Somarriba, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M. Mire, Li Jiang, Mariella G. Filbin

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

弥漫性半球胶质瘤、H3G34R/V-突变体(DHG-H3G34)是缺乏靶向疗法的致命性脑肿瘤。它们起源于神经元间前体;然而,利用这一起源进行治疗的前景仍有待探索。在这里,我们沿着中间神经元谱系发育连续体划分了一个细胞层次,揭示了 DHG-H3G34 反映了中间神经元巢周围祖细胞流的空间模式,正如在人类大脑发育过程中所看到的那样。将这些发现与全基因组 CRISPR-Cas9 筛选相结合,确定了在神经元系祖细胞中上调的基因为主要依赖基因。在这些基因中,CDK6 是一个可靶向的脆弱基因:DHG-H3G34肿瘤细胞对CDK4/6抑制剂和CDK6特异性降解剂的敏感性增强,促进向更成熟的中间神经元样状态转变,减少肿瘤生长,延长异种移植存活期。值得注意的是,一名进展期DHG-H3G34患者在接受CDK4/6抑制剂治疗后,病情稳定了17个月。这项研究强调了DHG-H3G34特有的神经元间祖细胞样状态,即在特征性龛位中组织起来的神经元间祖细胞样状态,突出表明CDK6是一个有希望的临床可操作靶点。
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引用次数: 0
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
期刊
Cancer Cell
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