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Spatially resolved transcriptomics and graph-based deep learning improve accuracy of routine CNS tumor diagnostics.
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-29 DOI: 10.1038/s43018-024-00904-z
Michael Ritter, Christina Blume, Yiheng Tang, Areeba Patel, Bhuvic Patel, Natalie Berghaus, Jasim Kada Benotmane, Jan Kueckelhaus, Yahaya Yabo, Junyi Zhang, Elena Grabis, Giulia Villa, David Niklas Zimmer, Amir Khriesh, Philipp Sievers, Zaira Seferbekova, Felix Hinz, Vidhya M Ravi, Marcel Seiz-Rosenhagen, Miriam Ratliff, Christel Herold-Mende, Oliver Schnell, Juergen Beck, Wolfgang Wick, Andreas von Deimling, Moritz Gerstung, Dieter Henrik Heiland, Felix Sahm

The diagnostic landscape of brain tumors integrates comprehensive molecular markers alongside traditional histopathological evaluation. DNA methylation and next-generation sequencing (NGS) have become a cornerstone in central nervous system (CNS) tumor classification. A limiting requirement for NGS and methylation profiling is sufficient DNA quality and quantity, which restrict its feasibility. Here we demonstrate NePSTA (neuropathology spatial transcriptomic analysis) for comprehensive morphological and molecular neuropathological diagnostics from single 5-µm tissue sections. NePSTA uses spatial transcriptomics with graph neural networks for automated histological and molecular evaluations. Trained and evaluated across 130 participants with CNS malignancies and healthy donors across four medical centers, NePSTA predicts tissue histology and methylation-based subclasses with high accuracy. We demonstrate the ability to reconstruct immunohistochemistry and genotype profiling on tissue with minimal requirements, inadequate for conventional molecular diagnostics, demonstrating the potential to enhance tumor subtype identification with implications for fast and precise diagnostic workup.

{"title":"Spatially resolved transcriptomics and graph-based deep learning improve accuracy of routine CNS tumor diagnostics.","authors":"Michael Ritter, Christina Blume, Yiheng Tang, Areeba Patel, Bhuvic Patel, Natalie Berghaus, Jasim Kada Benotmane, Jan Kueckelhaus, Yahaya Yabo, Junyi Zhang, Elena Grabis, Giulia Villa, David Niklas Zimmer, Amir Khriesh, Philipp Sievers, Zaira Seferbekova, Felix Hinz, Vidhya M Ravi, Marcel Seiz-Rosenhagen, Miriam Ratliff, Christel Herold-Mende, Oliver Schnell, Juergen Beck, Wolfgang Wick, Andreas von Deimling, Moritz Gerstung, Dieter Henrik Heiland, Felix Sahm","doi":"10.1038/s43018-024-00904-z","DOIUrl":"https://doi.org/10.1038/s43018-024-00904-z","url":null,"abstract":"<p><p>The diagnostic landscape of brain tumors integrates comprehensive molecular markers alongside traditional histopathological evaluation. DNA methylation and next-generation sequencing (NGS) have become a cornerstone in central nervous system (CNS) tumor classification. A limiting requirement for NGS and methylation profiling is sufficient DNA quality and quantity, which restrict its feasibility. Here we demonstrate NePSTA (neuropathology spatial transcriptomic analysis) for comprehensive morphological and molecular neuropathological diagnostics from single 5-µm tissue sections. NePSTA uses spatial transcriptomics with graph neural networks for automated histological and molecular evaluations. Trained and evaluated across 130 participants with CNS malignancies and healthy donors across four medical centers, NePSTA predicts tissue histology and methylation-based subclasses with high accuracy. We demonstrate the ability to reconstruct immunohistochemistry and genotype profiling on tissue with minimal requirements, inadequate for conventional molecular diagnostics, demonstrating the potential to enhance tumor subtype identification with implications for fast and precise diagnostic workup.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066831","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
Author Correction: Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-26 DOI: 10.1038/s43018-025-00915-4
Yizhou Zhu, Hayan Lee, Shannon White, Annika K Weimer, Emma Monte, Aaron Horning, Stephanie A Nevins, Edward D Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V Karathanos, Melissa W Y Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J Greenleaf, Christina Curtis, James M Ford, Michael P Snyder
{"title":"Author Correction: Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.","authors":"Yizhou Zhu, Hayan Lee, Shannon White, Annika K Weimer, Emma Monte, Aaron Horning, Stephanie A Nevins, Edward D Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Roxanne Chiu, Rozelle Laquindanum, Thomas V Karathanos, Melissa W Y Chua, Meredith Mills, Uri Ladabaum, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J Greenleaf, Christina Curtis, James M Ford, Michael P Snyder","doi":"10.1038/s43018-025-00915-4","DOIUrl":"https://doi.org/10.1038/s43018-025-00915-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047355","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
Inhibition of ERα signaling induces lineage plasticity in vivo.
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-24 DOI: 10.1038/s43018-024-00897-9
{"title":"Inhibition of ERα signaling induces lineage plasticity in vivo.","authors":"","doi":"10.1038/s43018-024-00897-9","DOIUrl":"https://doi.org/10.1038/s43018-024-00897-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040340","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
TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states. TRIM28依赖的发育异质性通过不同的表观遗传状态决定癌症易感性。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-24 DOI: 10.1038/s43018-024-00900-3
Ilaria Panzeri, Luca Fagnocchi, Stefanos Apostle, Megan Tompkins, Emily Wolfrum, Zachary Madaj, Galen Hostetter, Yanqing Liu, Kristen Schaefer, Chih-Hsiang Yang, Alexis Bergsma, Anne Drougard, Erez Dror, Darrell P Chandler, Daniel Schramek, Timothy J Triche, John Andrew Pospisilik

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.

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引用次数: 0
Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-23 DOI: 10.1038/s43018-024-00889-9
Martina Sanlorenzo, Philipp Novoszel, Igor Vujic, Tommaso Gastaldi, Martina Hammer, Ourania Fari, Cristiano De Sa Fernandes, Alina D. Landau, Bilge V. Göcen-Oguz, Martin Holcmann, Babak Monshi, Klemens Rappersberger, Agnes Csiszar, Maria Sibilia
Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8+ T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors. Sanlorenzo et al. propose a strategy to boost immunotherapy by combining topically applied TLR7/8 agonists with systemic interferon-I, sensitizing dendritic cells to produce IL-12 for tumor clearance and an adaptive immune response at metastatic sites.
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引用次数: 0
Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability. 用切口酶靶向brca1缺陷PARP抑制剂耐药细胞,揭示了切口切除是一种癌症易感性。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-21 DOI: 10.1038/s43018-024-00902-1
Jenna M Whalen, Jillian Earley, Christi Wisniewski, Arthur M Mercurio, Sharon B Cantor

Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex-which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks. The sensitivity is caused by hyper-resection of nicks into extensive single-stranded regions that trigger cell death. Based on these findings and that nicks limit tumor formation in mice, we propose nickases as a tool for personalized medicine. Moreover, our findings indicate that restricting nick expansion is a critical function of the 53BP1-Shieldin complex.

缺乏BRCA1和BRCA2 (BRCA)遗传性乳腺癌基因的肿瘤对抗癌治疗表现出更高的敏感性,例如聚(adp -核糖)聚合酶1 (PARP1)抑制剂。然而,一旦出现耐药性,就缺乏治疗方法。利用CRISPR技术,我们发现,在brca1缺陷细胞中,53bp1 -屏蔽蛋白复合物(与PARP抑制剂的抗性有关)的缺失,通过增加DNA末端切除来增强同源重组,也增加了对DNA缺口的敏感性。这种敏感性是由于切口过度切除到广泛的单链区域,从而引发细胞死亡。基于这些发现和切口限制小鼠肿瘤形成,我们提出切口酶作为个性化医疗的工具。此外,我们的研究结果表明,限制缺口扩展是53bp1 - shield复合物的关键功能。
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引用次数: 0
Refining biomarker design in light of cancer evolution 根据癌症进化改进生物标志物设计。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-20 DOI: 10.1038/s43018-024-00884-0
Insights from the TRACERx cohort suggest that the ORACLE biomarker might help to improve molecular prognostication in patients with lung tumors by accounting for spatiogenomic intratumor heterogeneity.
{"title":"Refining biomarker design in light of cancer evolution","authors":"","doi":"10.1038/s43018-024-00884-0","DOIUrl":"10.1038/s43018-024-00884-0","url":null,"abstract":"Insights from the TRACERx cohort suggest that the ORACLE biomarker might help to improve molecular prognostication in patients with lung tumors by accounting for spatiogenomic intratumor heterogeneity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"20-21"},"PeriodicalIF":23.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008605","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
Publisher Correction: TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation. 发布者更正:TIGIT和PD-L1共阻断通过促进共刺激促进多能、非耗尽抗肿瘤T细胞的克隆扩增。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1038/s43018-025-00908-3
Katherine Nutsch, Karl L Banta, Thomas D Wu, Charles W Tran, Stephanie Mittman, Ellen Duong, Barzin Y Nabet, Yan Qu, Katherine Williams, Sören Müller, Namrata S Patil, Eugene Y Chiang, Ira Mellman
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引用次数: 0
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity. 线粒体呼吸复合体I亚基Ndufs4/6选择性缺陷导致肿瘤免疫原性。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1038/s43018-024-00895-x
Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

癌细胞经常重新连接其代谢以支持增殖并逃避免疫监视,但对可能增加免疫监视的代谢靶点知之甚少。在这里,我们展示了线粒体呼吸复合体I (CI)抑制的一种特殊手段,可以提高肿瘤的免疫原性和对免疫检查点阻断(ICB)的敏感性。在黑色素瘤和乳腺癌模型中,Ndufs4或Ndufs6的靶向基因缺失,而不是其他CI亚基,诱导免疫依赖性生长衰减。我们发现,Ndufs4的缺失诱导了主要组织相容性复合体(MHC) I类共激活剂Nlrc5和抗原呈递机制成分的表达,最明显的是H2-K1。mhc相关基因的诱导是由丙酮酸脱氢酶依赖的线粒体乙酰辅酶a积累驱动的,这导致Nlrc5和H2-K1启动子内组蛋白H3K27乙酰化的增加。综上所述,这项工作表明选择性CI抑制限制肿瘤生长,特异性靶向Ndufs4或Ndufs6增加T细胞监视和ICB反应性。
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引用次数: 0
Fine-tuning tumor immunogenicity with mitochondrial complex I. 线粒体复合体I微调肿瘤免疫原性。
IF 23.5 1区 医学 Q1 ONCOLOGY Pub Date : 2025-01-17 DOI: 10.1038/s43018-024-00874-2
Désirée Schatton, Christian Frezza
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引用次数: 0
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Nature cancer
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