Tmic-14. Tumor Evolution of Glioma Intrinsic Gene Expression Subtype Associates With Immunological Changes in the Microenvironment
Year: 2016
Type: conference-abstract
Abstract: GBM tumor cells along with the tumor microenvironment create a complex milieu that ultimately promotes tumor cell plasticity and disease progression. Here, we explored the properties of the microenvironment in different GBM expression subtypes and characterized the transition between molecular subtypes before and after therapeutic intervention. We improved the robustness of expression subtype classification system by leveraging IDH wild type glioblastomas (GBM) and derivative neurosphere models to define three tumor-intrinsic mRNA transcription phenotype amongst IDH wild type GBMs. We observed 34/369 samples activated more than one transcriptional subtype. Subclonal mutation rate was significantly higher (p-value=0.024) in samples with multiple subtypes, suggesting that increased intratumoral heterogeneity associates with increased transcriptional heterogeneity. We used an in-silico cytometry method to evaluate the cellular components of the tumor microenvironment and demonstrated that M2 macrophages/microglia are the most frequent type of immune cells in the glioma microenvironment, followed by CD4+ T lymphocytes. The M2 macrophage signature also showed a greater association with the MES subtype (13.4%) relative to the PN (4.6%) and CL (6.0%). There was also a significantly higher fraction of MES samples that expressed M1 macrophage (p-value=3.20E-5) and neutrophil (p-value=1.30E-9) signatures. In contrast, the activated natural killer T-cell signature (p–value=4.91E-2) was significantly reduced in the MES and resting memory CD4+ T cells (p-value=5.40E-7) were less frequently expressed in the PN. Longitudinal transcriptome analysis of 124 pairs of primary and recurrent glioma showed expression subtype is retained in 53% of cases with no proneural to mesenchymal transition being apparent. The MES subtype was most stable (64%) while the CL (47%) and PN (43%) phenotypes were less frequently retained. Inference of the tumor microenvironment through gene signatures revealed a decrease in invading monocytes but a subtype dependent increase in M2 macrophages/microglia cells after disease recurrence. Our longitudinal expression dataset can be accessed at http://recur.bioinfo.cnio.es/.
Source: Neuro-Oncology
Authors: Qianghu Wang, Xin Hu, Florian Muller, Hoon Kim, Massimo Squatrito, Tom Mikkelsen, Lisa Scarpace, Floris Barthel, Yu-Hsi Lin, Nikunj Satani, Emmanuel Martinez-Ledesma, Edward Chang, Adriana Olar, Baoli Hu, Ana deCarvalho, Eskil Eskilsson, Siyuan Zheng, Amy Heimberger, Erik Sulman, Do-Hyun Nam, Roel Verhaak
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2587549796