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PMID: 28697342 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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

Cancer cell ·Vol. 32 ·No. 1 ·2017-00-10 ·Pages 42-56.e6

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, Barthel F, Cho HJ, Lin YH, Satani N, Martinez-Ledesma E, Zheng S, Chang E, Sauvé CG, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz KR, Wang G, Eskilsson E, Hu J, Mikkelsen T, DePinho RA, Muller F, Heimberger AB, Sulman EP, Nam DH, Verhaak RGW

Abstract

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.

Keywords
disease recurrence glioblastoma immune cells macrophages/microglia mesenchymal subtype proneural to mesenchymal transition tumor evolution tumor microenvironment
MeSH Terms
Gene Expression Profiling Gene Expression Regulation, Neoplastic Glioblastoma/genetics,immunology,pathology Humans Phenotype Recurrence Survival Analysis T-Lymphocytes/immunology Tumor Microenvironment/immunology
Authors & Affiliations
34 authors, click to expand affiliations / ORCID
Wang Qianghu
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.
Hu Baoli
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hu Xin
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.
Kim Hoon
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.
Squatrito Massimo
Cancer Cell Biology Programme, Seve Ballesteros Foundation Brain Tumor Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.
Scarpace Lisa
Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
deCarvalho Ana C
Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
Lyu Sali
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.
Li Pengping
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.
Li Yan
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.
Barthel Floris
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.
Cho Hee Jin
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.
Lin Yu-Hsi
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Satani Nikunj
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Martinez-Ledesma Emmanuel
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Zheng Siyuan
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chang Edward
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sauvé Charles-Etienne Gabriel
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Olar Adriana
Departments of Pathology and Laboratory Medicine, Neurosurgery Medical University of South Carolina, and Hollings Cancer Center, Charleston, SC 29425, USA.
Lan Zheng D
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Finocchiaro Gaetano
Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milano, Italy.
Phillips Joanna J
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Berger Mitchel S
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Gabrusiewicz Konrad R
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wang Guocan
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eskilsson Eskil
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hu Jian
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mikkelsen Tom
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
DePinho Ronald A
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Muller Florian
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.
Heimberger Amy B
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sulman Erik P
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. Electronic address: [email protected].
Nam Do-Hyun
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. Electronic address: [email protected].
Verhaak Roel G W
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. Electronic address: [email protected].
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2017.06.003
Email
[email protected]
[email protected]
[email protected]
Published
2017-00-10
Pages
42-56.e6
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC5599156
Subset
IM
Grants
NCI NIH HHS · R01 CA120813 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA190121 · United States
NCI NIH HHS · P30 CA034196 · United States
NCI NIH HHS · K99 CA194289 · United States
NCI NIH HHS · R00 CA194289 · United States
NCI NIH HHS · P50 CA097257 · United States
NCI NIH HHS · P50 CA127001 · United States
Corrections
ErratumIn
PMID: 29316430
External Links
PubMed source DOI: 10.1016/j.ccell.2017.06.003 PMC Full Text View journal details
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