Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.,Cancer Cell

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Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-07-10 , DOI: 10.1016/j.ccell.2017.06.003
Qianghu Wang ₁ , Baoli Hu ₂ , Xin Hu ₃ , Hoon Kim ₄ , Massimo Squatrito ₅ , Lisa Scarpace ₆ , Ana C deCarvalho ₆ , Sali Lyu ₇ , Pengping Li ₇ , Yan Li ₇ , Floris Barthel ₄ , Hee Jin Cho ₈ , Yu-Hsi Lin ₉ , Nikunj Satani ₉ , Emmanuel Martinez-Ledesma ₁₀ , Siyuan Zheng ₁₀ , Edward Chang ₁₀ , Charles-Etienne Gabriel Sauvé ₂ , Adriana Olar ₁₁ , Zheng D Lan ₂ , Gaetano Finocchiaro ₁₂ , Joanna J Phillips ₁₃ , Mitchel S Berger ₁₃ , Konrad R Gabrusiewicz ₁₄ , Guocan Wang ₂ , Eskil Eskilsson ₁₀ , Jian Hu ₂ , Tom Mikkelsen ₁₅ , Ronald A DePinho ₂ , Florian Muller ₁₆ , Amy B Heimberger ₁₄ , Erik P Sulman ₁₇ , Do-Hyun Nam ₁₈ , Roel G W Verhaak ₁₉

Affiliation

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas-Houston Graduate School in Biomedical Sciences, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Cancer Cell Biology Programme, Seve Ballesteros Foundation Brain Tumor Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.
Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China; Collaborative Innovation Center for Cardiovascular Disease, Nanjing Medical University, Nanjing 211166, China.
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Departments of Pathology and Laboratory Medicine, Neurosurgery Medical University of South Carolina, and Hollings Cancer Center, Charleston, SC 29425, USA.
Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milano, Italy.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea; Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

中文翻译：

胶质瘤内在基因表达亚型的肿瘤演变与微环境中的免疫学变化相关。

我们利用IDH野生型胶质母细胞瘤，衍生神经球和单细胞基因表达谱来定义三种肿瘤内在的转录亚型，分别称为前神经，间充质和经典。转录组亚型多样性与肿瘤内异质性增加和肿瘤微环境的存在有关。在计算机细胞分选中，在神经胶质瘤微环境中鉴定出巨噬细胞/小胶质细胞，CD4 + T淋巴细胞和嗜中性粒细胞。NF1缺乏症导致肿瘤相关的巨噬细胞/小胶质细胞浸润增加。纵向转录组分析表明，在55％的病例中保留了表达亚型。基于基因特征的肿瘤微环境推论显示，疾病复发后侵袭单核细胞减少，巨噬细胞/小胶质细胞亚型依赖性增加。诊断或复发时与CD8 + T细胞富集有关的超突变。M2巨噬细胞检测的频率与放疗后短期复发有关。

更新日期：2017-07-11

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