Multi-scale signaling and tumor evolution in high-grade gliomas

IF 48.8 1区 医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-07-08 DOI:10.1016/j.ccell.2024.06.004
Jingxian Liu, Song Cao, Kathleen J. Imbach, Marina A. Gritsenko, Tung-Shing M. Lih, Jennifer E. Kyle, Tomer M. Yaron-Barir, Zev A. Binder, Yize Li, Ilya Strunilin, Yi-Ting Wang, Chia-Feng Tsai, Weiping Ma, Lijun Chen, Natalie M. Clark, Andrew Shinkle, Nataly Naser Al Deen, Wagma Caravan, Andrew Houston, Faria Anjum Simin, Li Ding
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Abstract

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

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高级别胶质瘤的多尺度信号传导与肿瘤演化
尽管对胶质母细胞瘤(GBM)基因组异常的研究已有十多年历史,但其 5 年生存率仍低于 5%。我们试图通过将蛋白质组学、代谢组学、脂质组学、翻译后修饰(PTM)与基因组学和转录组学测量结合起来,揭示支配肿瘤发生和进化的多尺度调控相互作用,从而扩展由IDH野生型GBM和IDH突变型4级星形细胞瘤组成的高级别胶质瘤的分子图谱。对228个肿瘤(212个GBM和16个4级IDH突变星形细胞瘤),包括28个复发肿瘤,以及18个正常脑样本和14个脑转移瘤作为比较对象,应用14个蛋白质组学和代谢组学平台,揭示了异质性上游改变在蛋白质组学和代谢组学水平上汇聚到共同的下游事件,以及复发时蛋白质-蛋白质相互作用和糖基化位点占位的变化。PTPN11上反复出现的基因改变和磷酸化事件映射到重要的三维调控域,表明PTPN11信号传导在高级别胶质瘤中发挥着核心作用。
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来源期刊
Cancer Cell
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.
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