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Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.

ABSTRACT: Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n = 55 and n = 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the "metasignature" for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers.

SUBMITTER: Horvath S

PROVIDER: S-EPMC1635024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Glioblastoma multiforme (GBM) is a deadly brain tumour with minimal survival rates due to the ever-expanding heterogeneity, chemo and radioresistance. Kinases are known to crucially drive GBM pathology; however, a rationale therapeutic combination that can simultaneously inhibit multiple kinases has not yet emerged successfully. Results Here, we analyzed the GBM patient data from several publicly available repositories and deduced hub GBM kinases, most of which were identified to be SUMOylated by SUMO2/3 isoforms. Not only the hub kinases but a significant proportion of GBM upregulated genes involved in proliferation, metastasis, invasion, epithelial-mesenchymal transition, stemness, DNA repair, stromal and macrophages maintenance were also identified to be the targets of SUMO2 isoform. Correlatively, high expression of SUMO2 isoform was found to be significantly associated with poor patient survival. Conclusions Although many natural products and drugs are evidenced to target general SUMOylation, however, our meta-analysis strongly calls for the need to design SUMO2/3 or even better SUMO2 specific inhibitors and also explore the SUMO2 transcription inhibitors for universally potential, physiologically non-toxic anti-GBM drug therapy. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02279-y. Highlights The major highlights of this study are as follows: Key upregulated hub kinases and coding genes in GBM are found to be targets of SUMO2 conjugation. SUMO2 is significantly expressed in adult primary and recurrent GBMs as well as in pediatric GBM tumours. Orthotropic xenografts from adult and pediatric GBMs confirm high expression of SUMO2 in GBM tumour samples. SUMO2 is significantly associated with patient survival plot and pan-cancer cell fitness. Rationale design of SUMO2 inhibitors or search for its transcriptional inhibitors is urgently required through industry-academia collaboration for an anti-GBM and potentially pan-cancer therapeutics. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02279-y.

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Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.

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