Pub Date : 2024-09-12DOI: 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。
{"title":"Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain","authors":"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","doi":"10.1016/j.ccell.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.015","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"5 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171424","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 : 2024-09-09DOI: 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.
{"title":"Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow","authors":"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","doi":"10.1016/j.ccell.2024.08.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.008","url":null,"abstract":"<p>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 <em>in vivo</em>. 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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158717","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 : 2024-09-09DOI: 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.
{"title":"Assessing clonal changes in T cells over time following immunotherapy is a breeze with Cyclone","authors":"Anthony R. Cillo, John M. Kirkwood","doi":"10.1016/j.ccell.2024.08.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.014","url":null,"abstract":"<p>Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of <em>Cancer Cell</em>, Wang et al.<span><span><sup>1</sup></span></span> report dynamics and transcriptional states of CD8<sup>+</sup> 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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"72 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158715","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 : 2024-09-09DOI: 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.
{"title":"Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence","authors":"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","doi":"10.1016/j.ccell.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.012","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"18 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158716","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 : 2024-09-09DOI: 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.
{"title":"Classifying cancer-associated fibroblasts—The good, the bad, and the target","authors":"Lena Cords, Natalie de Souza, Bernd Bodenmiller","doi":"10.1016/j.ccell.2024.08.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.011","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"21 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158714","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}
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.
{"title":"Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer","authors":"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","doi":"10.1016/j.ccell.2024.08.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.013","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"48 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158718","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 : 2024-09-09Epub Date: 2024-08-15DOI: 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
{"title":"Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma.","authors":"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","doi":"10.1016/j.ccell.2024.07.012","DOIUrl":"10.1016/j.ccell.2024.07.012","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1630"},"PeriodicalIF":48.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995413","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 : 2024-09-05DOI: 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.
{"title":"Integrated electrophysiological and genomic profiles of single cells reveal spiking tumor cells in human glioma","authors":"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","doi":"10.1016/j.ccell.2024.08.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.009","url":null,"abstract":"<p>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 (IDH<sup>mut</sup>) 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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142863","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 : 2024-09-03DOI: 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.
{"title":"GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant","authors":"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","doi":"10.1016/j.ccell.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.006","url":null,"abstract":"<p>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.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"3 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123931","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 : 2024-08-29DOI: 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
{"title":"Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy","authors":"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","doi":"10.1016/j.ccell.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.004","url":null,"abstract":"No Abstract","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090444","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}