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. Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 42-56.e6 |
| Journal | Cancer Cell |
| Volume | 32 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 10 2017 |
| Externally published | Yes |
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Keywords
- disease recurrence
- glioblastoma
- immune cells
- macrophages/microglia
- mesenchymal subtype
- proneural to mesenchymal transition
- tumor evolution
- tumor microenvironment
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
Cite this
Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. / Wang, Qianghu; Hu, Baoli; Hu, Xin; Kim, Hoon; Squatrito, Massimo; Scarpace, Lisa; deCarvalho, Ana C.; Lyu, Sali; Li, Pengping; Li, Yan; Barthel, Floris; Cho, Hee Jin; Lin, Yu Hsi; Satani, Nikunj; Martinez-Ledesma, Emmanuel; Zheng, Siyuan; Chang, Edward; Sauvé, Charles Etienne Gabriel; Olar, Adriana; Lan, Zheng D.; Finocchiaro, Gaetano; Phillips, Joanna J.; Berger, Mitchel S.; Gabrusiewicz, Konrad R.; Wang, Guocan; Eskilsson, Eskil; Hu, Jian; Mikkelsen, Tom; DePinho, Ronald A.; Muller, Florian; Heimberger, Amy B.; Sulman, Erik P.; Nam, Do Hyun; Verhaak, Roel G.W.
In: Cancer Cell, Vol. 32, No. 1, 10.07.2017, p. 42-56.e6.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment
AU - Wang, Qianghu
AU - Hu, Baoli
AU - Hu, Xin
AU - Kim, Hoon
AU - Squatrito, Massimo
AU - Scarpace, Lisa
AU - deCarvalho, Ana C.
AU - Lyu, Sali
AU - Li, Pengping
AU - Li, Yan
AU - Barthel, Floris
AU - Cho, Hee Jin
AU - Lin, Yu Hsi
AU - Satani, Nikunj
AU - Martinez-Ledesma, Emmanuel
AU - Zheng, Siyuan
AU - Chang, Edward
AU - Sauvé, Charles Etienne Gabriel
AU - Olar, Adriana
AU - Lan, Zheng D.
AU - Finocchiaro, Gaetano
AU - Phillips, Joanna J.
AU - Berger, Mitchel S.
AU - Gabrusiewicz, Konrad R.
AU - Wang, Guocan
AU - Eskilsson, Eskil
AU - Hu, Jian
AU - Mikkelsen, Tom
AU - DePinho, Ronald A.
AU - Muller, Florian
AU - Heimberger, Amy B.
AU - Sulman, Erik P.
AU - Nam, Do Hyun
AU - Verhaak, Roel G.W.
PY - 2017/7/10
Y1 - 2017/7/10
N2 - 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. Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.
AB - 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. Wang et al. define three IDH wild-type glioblastoma-intrinsic gene expression subtypes, which are partly shaped by the tumor immune environment. NF1 deficiency results in increased macrophage/microglia infiltration. Comparison of matched primary and recurrent tumors reveals frequent expression subtype changes.
KW - disease recurrence
KW - glioblastoma
KW - immune cells
KW - macrophages/microglia
KW - mesenchymal subtype
KW - proneural to mesenchymal transition
KW - tumor evolution
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85027444208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027444208&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2017.06.003
DO - 10.1016/j.ccell.2017.06.003
M3 - Article
VL - 32
SP - 42-56.e6
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 1
ER -