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A transcriptional module initiates and maintains mesenchymal transformation in brain tumors [human data]

ABSTRACT: Using a novel combination of cellular-network reverse-engineering algorithms and experimental validation assays, we identified a transcriptional module, including six transcription factors that synergistically regulates the mesenchymal signature of malignant glioma. This is a poorly understood molecular phenotype, never observed in normal neural tissue. It represents the hallmark of tumor aggressiveness in high-grade glioma, and its upstream regulation is so far unknown. Overall, the newly discovered transcriptional module regulates >74% of the signature genes, while two of its transcription factors (C/EBPβ and Stat3) display features of initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPβ and Stat3 is sufficient to reprogram neural stem cells along the aberrant mesenchymal lineage, while simultaneously suppressing differentiation along the default neural lineages (neuronal and glial). Conversely, silencing the two transcription factors in human glioma cell lines and glioblastoma-derived tumor initiating cells leads to collapse of the mesenchymal signature with corresponding loss of tumor aggressiveness in vitro and in immunodeficient mice after intracranial injection. In human tumor samples, combined expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation of primary glioma and is a predictor of poor clinical outcome. Taken together, these results reveal that activation of a small regulatory module – inferred from the accurate reconstruction of transcriptional networks – is necessary and sufficient to initiate and maintain an aberrant phenotypic state in eukaryotic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19114 | GEO | 2010/02/12

SECONDARY ACCESSION(S): PRJNA129055

REPOSITORIES: GEO

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Project description:Wiskott-Aldrich syndrome (WAS) predisposes patients to leukemia and lymphoma. WAS is caused by mutations in the protein WASP which impair its interaction with the WIPF1 protein. Here, we aim to identify a module of WIPF1-coexpressed genes and to assess its use as a prognostic signature for colorectal cancer, glioma, and breast cancer patients. Two public colorectal cancer microarray data sets were used for discovery and validation of the WIPF1 co-expression module. Based on expression of the WIPF1 signature, we classified more than 400 additional tumors with microarray data from our own experiments or from publicly available data sets according to their WIPF1 signature expression. This allowed us to separate patient populations for colorectal cancers, breast cancers, and gliomas for which clinical characteristics like survival times and times to relapse were analyzed. Groups of colorectal cancer, breast cancer, and glioma patients with low expression of the WIPF1 co-expression module generally had a favorable prognosis. In addition, the majority of WIPF1 signature genes are individually correlated with disease outcome in different studies. Literature gene network analysis revealed that among WIPF1 co-expressed genes known direct transcriptional targets of c-myc, ESR1 and p53 are enriched. The mean expression profile of WIPF1 signature genes is correlated with the profile of a proliferation signature. The WIPF1 signature is the first microarray-based prognostic expression signature primarily developed for colorectal cancer that is instrumental in other tumor types: low expression of the WIPF1 module is associated with better prognosis. We used microarrays for the validation of a WIPF1 co-expression module which was developed on two publically available datasets. Keywords: disease state analysis For the generation of our own microarray data set, 62 CRC patients undergoing elective standard oncological resection at the Department of General, Vascular and Thoracic Surgery, Campus Benjamin Franklin, Charité, were prospectively recruited.

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A transcriptional module initiates and maintains mesenchymal transformation in brain tumors [human data]

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