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Published on: January 9, 2019
Heterogeneous activation of the TGFbeta pathway in glioblastomas identified by gene expression-based classification
1Biomarker R&D, Scios Inc, Fremont, California, USA. lxu@its.jnj.com
Background:
TGFbeta has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFbeta overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFbeta signaling to gain a comprehensive view of TGFbeta activation in large cohorts of human glioma patients.
Methods:
TGFbeta activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome. To systematically examine the status of TGFbeta activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFbeta stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGFbeta activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets.
Results:
Unsupervised and supervised classification using the TGFbeta-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFbeta activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFbeta activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFbeta activation, while the rest showed a weak TGFbeta transcriptional response.
Conclusion:
Our findings suggest heterogeneous TGFbeta activation in glioblastomas, which may cause potential differences in responses to anti-TGFbeta therapies in these two distinct subgroups of glioblastomas patients.
Insights
Transforming growth factor-beta (TGFbeta) signaling is heterogeneous in glioblastomas. Two distinct patient subgroups with varying TGFbeta activation levels were identified, impacting potential anti-TGFbeta therapy responses.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Transforming growth factor-beta (TGFbeta) is a key signaling pathway implicated in glioblastoma development.
- Aberrant TGFbeta signaling is frequently observed in high-grade gliomas, but a comprehensive analysis of its components in patient cohorts is lacking.
Purpose of the Study:
- To systematically investigate the status of TGFbeta signaling activation in human glioblastoma and high-grade glioma patients.
- To identify distinct subgroups of glioblastomas based on TGFbeta transcriptional response patterns.
Main Methods:
- Compiled a gene set of TGFbeta-responsive genes from cell culture and animal studies.
- Analyzed two independent glioma microarray datasets using unsupervised and supervised classification.
- Assessed TGFbeta activation levels based on transcriptional responses in glioblastoma samples.
Main Results:
- TGFbeta activation varied across high-grade gliomas.
- Two distinct glioblastoma subgroups were identified based on TGFbeta transcriptional response.
- Approximately 62% of glioblastomas exhibited strong TGFbeta activation, while the remainder showed weak activation.
Conclusions:
- Glioblastoma exhibits heterogeneous TGFbeta activation.
- Distinct subgroups of glioblastoma patients may respond differently to anti-TGFbeta therapies.
