首页 > 最新文献

Nature cancer最新文献

英文 中文
Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma 肾细胞癌对免疫检查点抑制异常反应的免疫基因组决定因素。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-09 DOI: 10.1038/s43018-024-00896-w
Tejas Jammihal, Renee Maria Saliby, Chris Labaki, Hanna Soulati, Juan Gallegos, Arnau Peris, Dustin McCurry, Chunlei Yu, Valisha Shah, Deepak Poduval, Talal El Zarif, Nourhan El Ahmar, Yasmin Nabil Laimon, Marc Eid, Aseman Bagheri Sheshdeh, Katherine M. Krajewski, Florian A. Büttner, Matthias Schwab, Daniel Heng, Rafael C. Casellas, Kunal Rai, Niki M. Zacharias Millward, Pavlos Msaouel, Jose Karam, Sabina Signoretti, Eliezer Van Allen, Toni K. Choueiri, David A. Braun, Sachet A. Shukla
Immune checkpoint inhibitors can lead to ‘exceptional’, durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC. Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.
免疫检查点抑制剂可在一小部分人群中导致“异常”、持久的反应。然而,转移性透明细胞肾细胞癌(mccRCC)免疫治疗异常反应(ER)的分子基础尚未得到很好的表征。在这里,我们分析了接受标准免疫疗法治疗的mccRCC患者的治疗前基因组和转录组学数据:(1)联合使用程序性细胞死亡蛋白和配体1 (PD1/PDL1)和细胞毒性T淋巴细胞相关蛋白4抑制剂(IO/IO)或(2)联合使用PD1/PDL1和血管内皮生长因子(VEGF)受体抑制剂(IO/VEGF)。在IO/IO队列中,ER患者的克隆新抗原载量明显更高。在IO/VEGF队列中,ER参与者表现出B细胞受体信号相关通路的强烈富集,三级淋巴样结构(TLS)特征和代谢活性增加的证据。我们的研究结果表明,ER可能与肿瘤微环境中克隆性新抗原驱动的细胞毒性T细胞反应和TLS形成有关。结合T细胞定向和B细胞定向抗肿瘤免疫的治疗组合对于实现基于io的ccRCC治疗的特殊益处可能是重要的。
{"title":"Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma","authors":"Tejas Jammihal, Renee Maria Saliby, Chris Labaki, Hanna Soulati, Juan Gallegos, Arnau Peris, Dustin McCurry, Chunlei Yu, Valisha Shah, Deepak Poduval, Talal El Zarif, Nourhan El Ahmar, Yasmin Nabil Laimon, Marc Eid, Aseman Bagheri Sheshdeh, Katherine M. Krajewski, Florian A. Büttner, Matthias Schwab, Daniel Heng, Rafael C. Casellas, Kunal Rai, Niki M. Zacharias Millward, Pavlos Msaouel, Jose Karam, Sabina Signoretti, Eliezer Van Allen, Toni K. Choueiri, David A. Braun, Sachet A. Shukla","doi":"10.1038/s43018-024-00896-w","DOIUrl":"10.1038/s43018-024-00896-w","url":null,"abstract":"Immune checkpoint inhibitors can lead to ‘exceptional’, durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC. Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 2","pages":"372-384"},"PeriodicalIF":23.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952008","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
Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer 持续的复制应激耐受性和克隆T细胞反应区分胰腺癌的肝和肺复发和预后。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-09 DOI: 10.1038/s43018-024-00881-3
Jason M. Link, Jennifer R. Eng, Carl Pelz, Kevin MacPherson-Hawthorne, Patrick J. Worth, Shamaline Sivagnanam, Dove J. Keith, Sydney Owen, Ellen M. Langer, Alison Grossblatt-Wait, Gustavo Salgado-Garza, Allison L. Creason, Sara Protzek, Julian Egger, Hannah Holly, Michael B. Heskett, Koei Chin, Nell Kirchberger, Konjit Betre, Elmar Bucher, David Kilburn, Zhi Hu, Michael W. Munks, Isabel A. English, Motoyuki Tsuda, Jeremy Goecks, Emek Demir, Andrew C. Adey, Adel Kardosh, Charles D. Lopez, Brett C. Sheppard, Alex Guimaraes, Brian Brinkerhoff, Terry K. Morgan, Gordon B. Mills, Lisa M. Coussens, Jonathan R. Brody, Rosalie C. Sears
Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. Sears and colleagues found that ongoing replication stress pathways and T cell clonal responses differentiate liver and lung recurrence and are associated with different clinical outcomes in the context of pancreatic ductal adenocarcinoma.
如果转移性胰腺导管腺癌扩散到肺部而不是肝脏,患者的存活时间会更长。在这里,我们生成了重叠的多组学数据集,以确定区分疾病发生肝转移的患者(肝脏队列)和疾病发生肺转移而无肝转移的患者(肺队列)的分子和细胞特征。肺部队列患者比肝脏队列患者存活时间更长,尽管具有相同的肿瘤亚型。我们开发了一个原发性嗜器官性(pORG)基因集,富集于肝组与肺组原发性肿瘤。我们在高pORG/肝脏队列肿瘤中发现了持续的复制应激反应途径,而低pORG/肺队列肿瘤具有更高的淋巴细胞密度和共享的T细胞克隆反应。我们的研究表明,嗜肝性胰腺导管腺癌与对持续复制应激的耐受性、有限的肿瘤免疫和不太有利的结果有关,而低复制应激、嗜肺性/嗜肝性肿瘤与活跃的肿瘤免疫有关,这可能解释了有利的结果。
{"title":"Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer","authors":"Jason M. Link, Jennifer R. Eng, Carl Pelz, Kevin MacPherson-Hawthorne, Patrick J. Worth, Shamaline Sivagnanam, Dove J. Keith, Sydney Owen, Ellen M. Langer, Alison Grossblatt-Wait, Gustavo Salgado-Garza, Allison L. Creason, Sara Protzek, Julian Egger, Hannah Holly, Michael B. Heskett, Koei Chin, Nell Kirchberger, Konjit Betre, Elmar Bucher, David Kilburn, Zhi Hu, Michael W. Munks, Isabel A. English, Motoyuki Tsuda, Jeremy Goecks, Emek Demir, Andrew C. Adey, Adel Kardosh, Charles D. Lopez, Brett C. Sheppard, Alex Guimaraes, Brian Brinkerhoff, Terry K. Morgan, Gordon B. Mills, Lisa M. Coussens, Jonathan R. Brody, Rosalie C. Sears","doi":"10.1038/s43018-024-00881-3","DOIUrl":"10.1038/s43018-024-00881-3","url":null,"abstract":"Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. Sears and colleagues found that ongoing replication stress pathways and T cell clonal responses differentiate liver and lung recurrence and are associated with different clinical outcomes in the context of pancreatic ductal adenocarcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"123-144"},"PeriodicalIF":23.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of CDKN2A loss on evolution of esophageal adenocarcinoma depend on context and time CDKN2A缺失对食管癌演变的影响取决于环境和时间。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-07 DOI: 10.1038/s43018-024-00877-z
Loss of CDKN2A is known to drive the progression of several cancers, including esophageal adenocarcinoma (EAC). Genetic analyses of samples of Barrett’s esophagus (EAC precursor condition) show that early loss of CDKN2A delays EAC initiation. Moreover, the concomitant loss of other genes in the same chromosomal locus has different effects depending on context.
{"title":"Effects of CDKN2A loss on evolution of esophageal adenocarcinoma depend on context and time","authors":"","doi":"10.1038/s43018-024-00877-z","DOIUrl":"10.1038/s43018-024-00877-z","url":null,"abstract":"Loss of CDKN2A is known to drive the progression of several cancers, including esophageal adenocarcinoma (EAC). Genetic analyses of samples of Barrett’s esophagus (EAC precursor condition) show that early loss of CDKN2A delays EAC initiation. Moreover, the concomitant loss of other genes in the same chromosomal locus has different effects depending on context.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"22-23"},"PeriodicalIF":23.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951993","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
Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer CDKN2A和其他9p21基因缺失在食管癌进化过程中的背景依赖性作用
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-03 DOI: 10.1038/s43018-024-00876-0
Piyali Ganguli, Celia C. Basanta, Amelia Acha-Sagredo, Hrvoje Misetic, Maria Armero, Akram Mendez, Aeman Zahra, Ginny Devonshire, Gavin Kelly, Adam Freeman, Mary Green, Emma Nye, Anita Bichisecchi, Paola Bonfanti, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Manuel Rodriguez-Justo, Jo Spencer, Rebecca C. Fitzgerald, Francesca D. Ciccarelli
CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE through context-dependent effects on cell cycle, oxidative phosphorylation and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BE, but not EAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management. Ganguli et al. show that CDKN2A loss in Barrett’s esophagus prevents esophageal adenocarcinoma initiation by counterselecting subsequent TP53 loss and report context-dependent effects of 9p21 gene co-deletions on disease progression.
CDKN2A是一种位于染色体9p21上的肿瘤抑制因子,在巴雷特食管(BE)和食管腺癌(EAC)中经常丢失。CDKN2A和其他9p21基因共缺失如何影响EAC进化仍有待研究。我们利用匹配的基因组、转录组学和临床数据,探讨了9p21缺失对EACs、癌症进展者和非进展者的影响。尽管它具有癌症驱动作用,但BE中CDKN2A的缺失通过反选择随后的TP53改变来阻止EAC的启动。通过对细胞周期、氧化磷酸化和干扰素反应的环境依赖性影响,9p21基因共缺失预测EAC患者的生存期较差,但不预测BE。使用大量转录组、RNAscope和高维组织成像的免疫定量分析显示,IFNE丢失会减少BE的免疫浸润,但不会减少EAC。从机制上讲,CDKN2A的缺失抑制了鳞状上皮的维持,导致更具侵袭性的表型。我们的研究证明了癌症基因在疾病进化过程中的环境依赖作用,以及癌症检测和患者管理的后果。
{"title":"Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer","authors":"Piyali Ganguli, Celia C. Basanta, Amelia Acha-Sagredo, Hrvoje Misetic, Maria Armero, Akram Mendez, Aeman Zahra, Ginny Devonshire, Gavin Kelly, Adam Freeman, Mary Green, Emma Nye, Anita Bichisecchi, Paola Bonfanti, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Manuel Rodriguez-Justo, Jo Spencer, Rebecca C. Fitzgerald, Francesca D. Ciccarelli","doi":"10.1038/s43018-024-00876-0","DOIUrl":"10.1038/s43018-024-00876-0","url":null,"abstract":"CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE through context-dependent effects on cell cycle, oxidative phosphorylation and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BE, but not EAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management. Ganguli et al. show that CDKN2A loss in Barrett’s esophagus prevents esophageal adenocarcinoma initiation by counterselecting subsequent TP53 loss and report context-dependent effects of 9p21 gene co-deletions on disease progression.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"158-174"},"PeriodicalIF":23.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1–HER3 signaling 循环肿瘤细胞可塑性通过神经调节蛋白1-HER3信号传导决定乳腺癌治疗耐药性。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-03 DOI: 10.1038/s43018-024-00882-2
Roberto Würth, Elisa Donato, Laura L. Michel, Massimo Saini, Lisa Becker, Tasneem Cheytan, Daria Doncevic, Tobias Messmer, Ewgenija Gutjahr, Rebecca Weber, Corinna Klein, Hamed Alborzinia, Umut Yildiz, Vanessa Vogel, Mario Hlevnjak, Polina Kozyulina, Sarah-Jane Neuberth, Paul Schwerd-Kleine, Sevinç Jakab, Nicole Pfarr, Arlou Kristina Angeles, Astrid K. Laut, Darja Karpova, Mattia Falcone, Olaf Hardt, Benjamin Theek, Celina V. Wagner, Mirjam Becker, Sabine Wagner, Martina Haselmayr, Anita Schmitt, Carsten Müller-Tidow, Sabine Riethdorf, Klaus Pantel, Marc Zapatka, Holger Sültmann, Carl Herrmann, Verena Thewes, Peter Lichter, Andreas Schneeweiss, Martin R. Sprick, Andreas Trumpp
Circulating tumor cells (CTCs) drive metastasis, the leading cause of death in individuals with breast cancer. Due to their low abundance in the circulation, robust CTC expansion protocols are urgently needed to effectively study disease progression and therapy responses. Here we present the establishment of long-term CTC-derived organoids from female individuals with metastatic breast cancer. Multiomics analysis of CTC-derived organoids along with preclinical modeling with xenografts identified neuregulin 1 (NRG1)–ERBB2 receptor tyrosine kinase 3 (ERBB3/HER3) signaling as a key pathway required for CTC survival, growth and dissemination. Genome-wide CRISPR activation screens revealed that fibroblast growth factor receptor 1 (FGFR1) signaling serves a compensatory function to the NRG1–HER3 axis and rescues NRG1 deficiency in CTCs. Conversely, NRG1–HER3 activation induced resistance to FGFR1 inhibition, whereas combinatorial blockade impaired CTC growth. The dynamic interplay between NRG1–HER3 and FGFR1 signaling reveals the molecular basis of cancer cell plasticity and clinically relevant strategies to target it. Our CTC organoid platform enables the identification and validation of patient-specific vulnerabilities and represents an innovative tool for precision medicine. Trumpp and colleagues develop a method to obtain long-term circulating tumor cell-derived organoids from individuals with metastatic breast cancer and identify the neuregulin 1–HER3 axis as important for organoid growth and a promising therapeutic target.
循环肿瘤细胞(ctc)驱动转移,是乳腺癌患者死亡的主要原因。由于它们在循环中的丰度较低,迫切需要强有力的CTC扩增方案来有效研究疾病进展和治疗反应。在这里,我们提出建立长期ctc来源的类器官从女性个体转移性乳腺癌。对CTC衍生类器官的多组学分析以及异种移植物临床前建模发现,神经调节蛋白1 (NRG1)-ERBB2受体酪氨酸激酶3 (ERBB3/HER3)信号通路是CTC存活、生长和传播所需的关键途径。全基因组CRISPR激活筛选显示,成纤维细胞生长因子受体1 (FGFR1)信号通路对NRG1- her3轴具有代偿功能,并可挽救CTCs中的NRG1缺陷。相反,NRG1-HER3激活诱导对FGFR1抑制的抗性,而联合阻断则会损害CTC的生长。NRG1-HER3和FGFR1信号传导之间的动态相互作用揭示了癌细胞可塑性的分子基础和临床相关的靶向策略。我们的CTC类器官平台能够识别和验证患者特定的脆弱性,代表了精准医疗的创新工具。
{"title":"Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1–HER3 signaling","authors":"Roberto Würth, Elisa Donato, Laura L. Michel, Massimo Saini, Lisa Becker, Tasneem Cheytan, Daria Doncevic, Tobias Messmer, Ewgenija Gutjahr, Rebecca Weber, Corinna Klein, Hamed Alborzinia, Umut Yildiz, Vanessa Vogel, Mario Hlevnjak, Polina Kozyulina, Sarah-Jane Neuberth, Paul Schwerd-Kleine, Sevinç Jakab, Nicole Pfarr, Arlou Kristina Angeles, Astrid K. Laut, Darja Karpova, Mattia Falcone, Olaf Hardt, Benjamin Theek, Celina V. Wagner, Mirjam Becker, Sabine Wagner, Martina Haselmayr, Anita Schmitt, Carsten Müller-Tidow, Sabine Riethdorf, Klaus Pantel, Marc Zapatka, Holger Sültmann, Carl Herrmann, Verena Thewes, Peter Lichter, Andreas Schneeweiss, Martin R. Sprick, Andreas Trumpp","doi":"10.1038/s43018-024-00882-2","DOIUrl":"10.1038/s43018-024-00882-2","url":null,"abstract":"Circulating tumor cells (CTCs) drive metastasis, the leading cause of death in individuals with breast cancer. Due to their low abundance in the circulation, robust CTC expansion protocols are urgently needed to effectively study disease progression and therapy responses. Here we present the establishment of long-term CTC-derived organoids from female individuals with metastatic breast cancer. Multiomics analysis of CTC-derived organoids along with preclinical modeling with xenografts identified neuregulin 1 (NRG1)–ERBB2 receptor tyrosine kinase 3 (ERBB3/HER3) signaling as a key pathway required for CTC survival, growth and dissemination. Genome-wide CRISPR activation screens revealed that fibroblast growth factor receptor 1 (FGFR1) signaling serves a compensatory function to the NRG1–HER3 axis and rescues NRG1 deficiency in CTCs. Conversely, NRG1–HER3 activation induced resistance to FGFR1 inhibition, whereas combinatorial blockade impaired CTC growth. The dynamic interplay between NRG1–HER3 and FGFR1 signaling reveals the molecular basis of cancer cell plasticity and clinically relevant strategies to target it. Our CTC organoid platform enables the identification and validation of patient-specific vulnerabilities and represents an innovative tool for precision medicine. Trumpp and colleagues develop a method to obtain long-term circulating tumor cell-derived organoids from individuals with metastatic breast cancer and identify the neuregulin 1–HER3 axis as important for organoid growth and a promising therapeutic target.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"67-85"},"PeriodicalIF":23.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The global impact of the COVID-19 pandemic on delays and disruptions in cancer care services: a systematic review and meta-analysis 2019冠状病毒病大流行对癌症护理服务延误和中断的全球影响:系统回顾和荟萃分析。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-02 DOI: 10.1038/s43018-024-00880-4
Richa Shah, Nader Mounir Hanna, Ching Ee Loo, Michael David, Allini Mafra, Hanna Fink, Ethna McFerran, Montse Garcia, Robabeh Ghodssighassemabadi, Suryakanta Acharya, Jean Niyibaga, Oliver Langselius, Clara Frick, Nwamaka Lasebikan, Jerome Vignat, Julia Steinberg, Suzanne Hughes, Colleen Elizabeth Kircher, Catherine Lindsay Goldie, Sam Egger, Richard Sullivan, Ophira Ginsburg, Freddie Bray, Michael Caruana, Harriet Hui, André Michel Ilbawi, Karen Canfell, Isabelle Soerjomataram
The coronavirus disease 2019 pandemic substantially impacted the delivery of cancer services and programs. Here we reviewed and synthesized the global scale and impact of pandemic-related delays and disruptions on cancer services, including diagnosis, diagnostic procedures, screening, treatment and supportive and palliative care. Based on data from 245 articles in 46 countries, we observed declines in the number of cancer screening participation (39.0%), diagnoses (23.0%), diagnostic procedures (24.0%) and treatment (28.0%), ranging from a 15.0% decline for radiotherapy to a 35.0% decline for systemic treatment during the pandemic compared to during the prepandemic period. Medium-human development index (HDI) category countries experienced greater reductions than high- and very-high-HDI countries. Missing data from low-HDI countries emphasize the need for increased investments in cancer surveillance and research in these settings. PROSPERO registration: CRD42022301816 Shah et al. conducted a systematic review and meta-analysis of the impact of COVID-19 pandemic-related disruptions to cancer healthcare services and reported reduced cancer screening, diagnosis and treatment of patients.
2019年冠状病毒病大流行严重影响了癌症服务和项目的提供。在这里,我们回顾并综合了与大流行相关的延迟和中断对癌症服务的全球规模和影响,包括诊断、诊断程序、筛查、治疗以及支持和姑息治疗。根据46个国家245篇文章的数据,我们观察到,与大流行前相比,大流行期间,癌症筛查参与(39.0%)、诊断(23.0%)、诊断程序(24.0%)和治疗(28.0%)的数量下降,从放射治疗下降15.0%到全身治疗下降35.0%不等。中等人类发展指数(HDI)类别国家比高和非常高人类发展指数国家减少得更多。低人类发展指数国家缺少的数据强调了在这些环境中需要增加对癌症监测和研究的投资。普洛斯彼罗注册号:CRD42022301816。
{"title":"The global impact of the COVID-19 pandemic on delays and disruptions in cancer care services: a systematic review and meta-analysis","authors":"Richa Shah, Nader Mounir Hanna, Ching Ee Loo, Michael David, Allini Mafra, Hanna Fink, Ethna McFerran, Montse Garcia, Robabeh Ghodssighassemabadi, Suryakanta Acharya, Jean Niyibaga, Oliver Langselius, Clara Frick, Nwamaka Lasebikan, Jerome Vignat, Julia Steinberg, Suzanne Hughes, Colleen Elizabeth Kircher, Catherine Lindsay Goldie, Sam Egger, Richard Sullivan, Ophira Ginsburg, Freddie Bray, Michael Caruana, Harriet Hui, André Michel Ilbawi, Karen Canfell, Isabelle Soerjomataram","doi":"10.1038/s43018-024-00880-4","DOIUrl":"10.1038/s43018-024-00880-4","url":null,"abstract":"The coronavirus disease 2019 pandemic substantially impacted the delivery of cancer services and programs. Here we reviewed and synthesized the global scale and impact of pandemic-related delays and disruptions on cancer services, including diagnosis, diagnostic procedures, screening, treatment and supportive and palliative care. Based on data from 245 articles in 46 countries, we observed declines in the number of cancer screening participation (39.0%), diagnoses (23.0%), diagnostic procedures (24.0%) and treatment (28.0%), ranging from a 15.0% decline for radiotherapy to a 35.0% decline for systemic treatment during the pandemic compared to during the prepandemic period. Medium-human development index (HDI) category countries experienced greater reductions than high- and very-high-HDI countries. Missing data from low-HDI countries emphasize the need for increased investments in cancer surveillance and research in these settings. PROSPERO registration: CRD42022301816 Shah et al. conducted a systematic review and meta-analysis of the impact of COVID-19 pandemic-related disruptions to cancer healthcare services and reported reduced cancer screening, diagnosis and treatment of patients.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"194-204"},"PeriodicalIF":23.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922109","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
Challenges and opportunities in training cancer researchers 培训癌症研究人员的挑战与机遇。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-02 DOI: 10.1038/s43018-024-00872-4
Brian Keith, Danny R. Welch, Nishtha Agarwal, Caroline Blair, Ifeanyi Beverly Chukwudozie, Lalita A. Shevde, Lawrence H. Boise, Kerry L. Burnstein, Toni M. Antalis, Kathleen L. O’Connor, Sorab N. Dalal, Sheridan Ellis, Harikrishna Nakshatri
Training the next generation of cancer researchers is essential for the cancer research enterprise. However, training programs and methods to evaluate their effectiveness vary greatly across the USA and other countries. Here we discuss strategies to enhance cancer education and processes by which training may be standardized.
{"title":"Challenges and opportunities in training cancer researchers","authors":"Brian Keith, Danny R. Welch, Nishtha Agarwal, Caroline Blair, Ifeanyi Beverly Chukwudozie, Lalita A. Shevde, Lawrence H. Boise, Kerry L. Burnstein, Toni M. Antalis, Kathleen L. O’Connor, Sorab N. Dalal, Sheridan Ellis, Harikrishna Nakshatri","doi":"10.1038/s43018-024-00872-4","DOIUrl":"10.1038/s43018-024-00872-4","url":null,"abstract":"Training the next generation of cancer researchers is essential for the cancer research enterprise. However, training programs and methods to evaluate their effectiveness vary greatly across the USA and other countries. Here we discuss strategies to enhance cancer education and processes by which training may be standardized.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 2","pages":"223-225"},"PeriodicalIF":23.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922103","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
Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion 硬脑膜免疫对脑脊液屏障侵袭的免疫抑制作用
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-12-20 DOI: 10.1038/s43018-024-00858-2
Jiaxu Zhao, Rui Zeng, Xiaohui Li, Ying Lu, Zuoyun Wang, Haibao Peng, Hao Chen, Minjie Fu, Ye Zhang, Yang Huang, Wenhan Chen, Xin Wang, Yun Guan, Wei Han, Ruofan Huang, Chengjun Yao, Zhiyong Qin, Lingchao Chen, Liang Chen, Xue Feng, Hanting Yang, Patrícia M. R. Pereira, Xuemei Tong, Bin Li, Qiangqiang Zhang, Yudan Chi
The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1–MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy. Zhao et al. find that a macrophage subset migrates from the dura matter to reshape the cerebrospinal fluid microenvironment and promote metastasis and show that the secreted phosphoprotein 1–matrix metallopeptidase 14 axis can be targeted to inhibit this.
脑脊液(CSF)边界容纳多种免疫细胞,允许外周细胞免疫监视。然而,脑脊液免疫细胞与浸润性癌细胞之间复杂的相互作用仍然知之甚少。在这里,我们使用命运图谱、纵向延时成像和多组学技术来研究巨噬细胞的精确起源、细胞串扰和分子景观,这些巨噬细胞有助于瘦脑膜转移(LM)的进展。机械上,我们发现硬脑膜衍生的lm相关巨噬细胞(dram)以基质金属蛋白酶14 (MMP14)依赖的方式迁移到CSF中。此外,我们发现dram需要癌细胞中分泌磷酸化蛋白1 (SPP1)的存在才能募集,从而形成以T细胞衰竭和失活为特征的免疫抑制微环境。相反,抑制SPP1-MMP14轴可以阻止巨噬细胞绕过边界屏障,阻止癌细胞生长,提高LM小鼠模型的存活率。我们的发现揭示了脑膜空间内先天免疫的一个意想不到的私人来源,揭示了脑脊液屏障功能障碍动力学,并提供了临床免疫治疗的潜在靶点。Zhao等人发现巨噬细胞亚群从硬脑膜迁移,重塑脑脊液微环境,促进转移,并表明分泌的磷酸化蛋白1 -基质金属肽酶14轴可被靶向抑制。
{"title":"Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion","authors":"Jiaxu Zhao, Rui Zeng, Xiaohui Li, Ying Lu, Zuoyun Wang, Haibao Peng, Hao Chen, Minjie Fu, Ye Zhang, Yang Huang, Wenhan Chen, Xin Wang, Yun Guan, Wei Han, Ruofan Huang, Chengjun Yao, Zhiyong Qin, Lingchao Chen, Liang Chen, Xue Feng, Hanting Yang, Patrícia M. R. Pereira, Xuemei Tong, Bin Li, Qiangqiang Zhang, Yudan Chi","doi":"10.1038/s43018-024-00858-2","DOIUrl":"10.1038/s43018-024-00858-2","url":null,"abstract":"The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1–MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy. Zhao et al. find that a macrophage subset migrates from the dura matter to reshape the cerebrospinal fluid microenvironment and promote metastasis and show that the secreted phosphoprotein 1–matrix metallopeptidase 14 axis can be targeted to inhibit this.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1940-1961"},"PeriodicalIF":23.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870516","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
Immunosuppressive dura-derived macrophages in leptomeningeal metastasis 免疫抑制硬脑膜源性巨噬细胞在小脑膜转移中的作用
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-12-20 DOI: 10.1038/s43018-024-00859-1
Michael Kilian, Francisco J. Quintana
Leptomeningeal metastases of solid tumors are associated with poor prognosis, limited treatment options and unclear immunosurveillance mechanisms. Dura-derived immunosuppressive macrophages are now shown to migrate to the cerebrospinal fluid, limiting anti-tumor CD8+ T cell responses in models of leptomeningeal metastasis.
实体瘤的轻脑膜转移与预后差、治疗选择有限和免疫监测机制不明确有关。硬脑膜来源的免疫抑制巨噬细胞现在被证明可以迁移到脑脊液中,在脑膜轻脑膜转移模型中限制抗肿瘤CD8+ T细胞反应。
{"title":"Immunosuppressive dura-derived macrophages in leptomeningeal metastasis","authors":"Michael Kilian, Francisco J. Quintana","doi":"10.1038/s43018-024-00859-1","DOIUrl":"10.1038/s43018-024-00859-1","url":null,"abstract":"Leptomeningeal metastases of solid tumors are associated with poor prognosis, limited treatment options and unclear immunosurveillance mechanisms. Dura-derived immunosuppressive macrophages are now shown to migrate to the cerebrospinal fluid, limiting anti-tumor CD8+ T cell responses in models of leptomeningeal metastasis.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1791-1792"},"PeriodicalIF":23.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870527","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
Radioligand cancer therapy comes to the fore 放射性配体癌症疗法崭露头角。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-12-17 DOI: 10.1038/s43018-024-00856-4
Vincenzo Giacco
{"title":"Radioligand cancer therapy comes to the fore","authors":"Vincenzo Giacco","doi":"10.1038/s43018-024-00856-4","DOIUrl":"10.1038/s43018-024-00856-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 12","pages":"1782-1782"},"PeriodicalIF":23.5,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847097","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
期刊
Nature cancer
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1