Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target
Open accessAbstract
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.
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Hubs can be key molecular drivers, such as transcriptional regulators that drive co-expression, or may annotate a module by reflecting its predominant biological role.
“Hubs can be key molecular drivers, such as transcriptional regulators that drive co-expression30,31, or they may annotate a module by reflecting the predominant biological role of the module.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [31]
ASPM expression is required for symmetric, proliferative divisions of neural stem/progenitor cells of the mammalian brain.
“ASPM expression has been shown to be required for symmetric, proliferative divisions of neural stem/progenitor cells of the mammalian brain (Fish et al., 2006; Horvath et al., 2006).”
From FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis (2009) · cites this paper as Horvath et al., 2006
Weighted gene co-expression network analyses were performed using recommended parameters from original analysis developers.
“Weighted gene co-expression network analyses were performed as described in Matarin et al. (2015), using the recommended parameters from the original analysis developers (Zhang and Horvath, 2005; Horvath et al., 2006; Oldham et al., 2006; Langfelder and Horvath, 2008).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Horvath et al., 2006
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- Authors
- Horvath, S., Zhang, B., Carlson, M., Lu, K. V., Zhu, S., Felciano, R. M., Laurance, M. F., Zhao, W., Qi, S., Chen, Z., Lee, Y., Scheck, A. C., Liau, L. M., Wu, H., Geschwind, D. H., Febbo, P. G., Kornblum, H. I., Cloughesy, T. F., Nelson, S. F., & Mischel, P. S.
- Affiliations
- Human Genetics,
- Departments of dPathology and Laboratory Medicine,
- Ingenuity Systems, Inc., 1700 Seaport Boulevard, Third Floor, Redwood City, CA 94063;
- Pharmacology, and
- St. Joseph's Hospital and Medical Center (US)
- Neurosurgery,
- University of California, Los Angeles (US)
- Duke University (US)
- Neurology,
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-11-14
- Volume
- 103
- Issue
- 46
- Pages
- 17402-17407
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1635024
- OpenAlex
- W2068229930
- Cited by
- 641
- References
- 46
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 27 · 2023: 24 · 2022: 21 · 2021: 40 · 2020: 51 · 2019: 39 · 2018: 32 · 2017: 36 · 2016: 33 · 2015: 25 · 2014: 32 · 2013: 62 · 2012: 43
- FWCI
- 13.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Accelerate Brain Cancer Cure
- Eli Lilly and Company
- Brain Tumor Funders' Collaborative
- Ziering Family Foundation
- Barrow Neurological Foundation
- National Institutes of Health (1r13ns043137-01, 5u54ca119347-03)
- University of California, Los Angeles
- National Cancer Institute (R01CA108633, CA 108633, U54-CA119347, CA 119347, T32CA009056)
- National Institute of Neurological Disorders and Stroke (R01NS050151, NS43137, NS 050151)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Keywords
- glioblastoma, ASPM, EGFRvIII, erlotinib, targeted therapy, breast cancer, neural stem cell proliferation, tumor cell proliferation, siRNA knockdown, weighted gene co-expression network analysis
- MeSH terms
- ELAV-Like Protein 2, Animals, Breast Neoplasms, Cells, Cultured, Glioblastoma, Humans, Nerve Tissue Proteins, Signal Transduction, Oncogene Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Profiling, RNA Interference, Mice, ELAV Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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