Protein-based classification reveals an immune-hot subtype in IDH mutant astrocytoma with worse prognosis

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-09-11 DOI:10.1016/j.ccell.2025.08.006

Jihong Tang, Wenhua Fan, Yuyan Ruan, Xing Liu, Fufang Qiu, Jie Feng, Guoshi Huang, Mengli Yan, Hui Wang, Quanhua Mu, Ran Liu, Yingxi Yang, Zhi Huang, Yimeng Qiao, Xuejie Wang, Yumeng Guo, Mingchen Yu, Ying Zhang, Ruichao Chai, Fan Wu, Jiguang Wang

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引用次数: 0

Abstract

Intertumoral heterogeneity complicates treatment of IDH-mutant astrocytoma. We analyze spatiotemporal multi-omics data and discover four clusters: adipogenesis/fatty-acid-metabolism (AFM), proliferative/progenitor (PPR), immune/mesenchymal-enriched (IME), and neuronal (NEU). PPR and IME are associated with poorer prognosis, a result validated in The Cancer Genome Atlas (TCGA) and a Chinese cohort of 273 IDH-mutant astrocytomas. Longitudinal analysis of 189 initial-recurrent pairs shows an evolutionary shift toward PPR/IME subtypes. Mechanistically, PPR is enriched for CDKN2A/B deletions, whereas IME features increased gemistocytic differentiation (GD) and infiltration by exhausted T cells and plasma cells. Spatial multi-omics link GD morphology to mesenchymal-like (MES-like) tumor cell aggregates and lymphocyte-rich niches. MES-like tumor cells in IME overexpress interferon-stimulated genes such as GBP1, which we show promotes proliferation and migration. Finally, we develop an AI-powered classifier for patient stratification. Our work delineates protein-based clustering of IDH-mutant astrocytoma and reveals an immune-hot subgroup that may inform therapeutic development.

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基于蛋白质的分类揭示了IDH突变型星形细胞瘤的免疫热亚型，预后较差

肿瘤间异质性使idh突变星形细胞瘤的治疗复杂化。我们分析了时空多组学数据，发现了四个集群：脂肪生成/脂肪酸代谢（AFM）、增殖/祖细胞（PPR）、免疫/间充质富集（IME）和神经元（NEU）。PPR和IME与较差的预后相关，这一结果在癌症基因组图谱（TCGA）和273例idh突变星形细胞瘤的中国队列中得到了验证。对189对初始复发基因对的纵向分析显示了向PPR/IME亚型的进化转变。从机制上讲，PPR富集CDKN2A/B缺失，而IME则增加了生殖细胞分化（GD）和耗竭的T细胞和浆细胞的浸润。空间多组学将GD形态与间充质样（mes样）肿瘤细胞聚集和富含淋巴细胞的生态位联系起来。IME中的mes样肿瘤细胞过表达干扰素刺激基因，如GBP1，我们发现它促进了增殖和迁移。最后，我们开发了一个用于患者分层的人工智能分类器。我们的工作描述了idh突变星形细胞瘤的基于蛋白质的聚类，并揭示了一个免疫热亚群，可能为治疗发展提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.