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

Authors:
Qianghu Wang
Qianghu Wang
Harbin Medical University
China
Baoli Hu
Baoli Hu
University of Texas MD Anderson Cancer Center
Houston | United States
Xin Hu
Xin Hu
National Institutes of Health
United States
Hoon Kim
Hoon Kim
Sunchon National University
South Korea
Massimo Squatrito
Massimo Squatrito
European Institute of Oncology
Italy
Lisa Scarpace
Lisa Scarpace
Henry Ford Hospital
United States
Ana C deCarvalho
Ana C deCarvalho
Henry Ford Hospital
United States
Sali Lyu
Sali Lyu
Key Laboratory of Human Functional Genomics of Jiangsu Province

Cancer Cell 2017 07;32(1):42-56.e6

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:

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599156PMC
July 2017
22 Reads

Publication Analysis

Top Keywords

gene expression
8
tumor microenvironment
8
cell sorting
4
sorting identified
4
silico cell
4
microenvironment silico
4
disease recurrence
4
identified macrophages/microglia
4
lymphocytes neutrophils
4
macrophages/microglia cells
4
cd4 lymphocytes
4
macrophages/microglia cd4
4
cells disease
4
recurrence hypermutation
4
presence tumor
4
inference revealed
4
subtype multiplicity
4
recurrence associated
4
transcriptomic subtype
4
correlated increased
4

Similar Publications

Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis.

Oncotarget 2015 Jun;6(17):15077-94

Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.

The most abundant populations of non-neoplastic cells in the glioblastoma (GBM) microenvironment are resident microglia, macrophages and infiltrating monocytes from the blood circulation. The mechanisms by which monocytes infiltrate into GBM, their fate following infiltration, and their role in GBM growth are not known. Here we tested the hypothesis that loss of the fractalkine receptor CX3CR1 in microglia and monocytes would affect gliomagenesis. Read More

View Article
June 2015

Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis.

Neuro Oncol 2017 Nov;19(12):1599-1606

Radiation Oncology and Metabolomics and Obstetrics/Gynecology, Beaumont Health, Royal Oak, Michigan.

Background: Glioblastoma represents an archetypal example of a heterogeneous malignancy. To understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in glioblastoma enriched using laser capture microdissection.

Methods: Raw gene-level values of fragments per kilobase of transcript per million reads mapped and the associated clinical data were acquired from the publicly available Ivy Glioblastoma Atlas Project database and analyzed using MetaboAnalyst (v3. Read More

View Article
November 2017

Detection of proneural/mesenchymal marker expression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression.

J Neurooncol 2015 Oct 14;125(1):33-41. Epub 2015 Aug 14.

Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Proneural and mesenchymal are two subtypes of glioblastoma identified by gene expression profiling. In this study, the primary aim was to detect markers to develop a clinically applicable method for distinguishing proneural and mesenchymal glioblastoma. The secondary aims were to investigate the temporospatial dynamics of these markers and to explore the association between these markers and the expression of chromatin-modifying genes. Read More

View Article
October 2015

Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology.

J Neurosurg 2011 Sep 10;115(3):505-11. Epub 2011 Jun 10.

Department of Neurosurgery, University of California, Los Angeles, California, USA.

Object: The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.

Methods: Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. Read More

View Article
September 2011