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Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression
Open accessAbstract
Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.
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“In line with these observations, it has been recently shown that BDNF produced by glioblastoma (GBM) differentiated cells acts on GBM stem cells, fostering their growth through paracrine signaling [258].”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [258]
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Metadata
- Authors
- Wang, X., Prager, B. C., Wu, Q., Kim, L. J. Y., Gimple, R. C., Shi, Y., Yang, K., Morton, A. R., Zhou, W., Zhu, Z., Obara, E. A. A., Miller, T. E., Song, A., Lai, S., Hubert, C. G., Jin, X., Huang, Z., Fang, X., Dixit, D., Tao, W., Zhai, K., Chen, C., Dong, Z., Zhang, G., Dombrowski, S. M., Hamerlik, P., Mack, S. C., Bao, S., & Rich, J. N.
- Affiliations
- University of California San Diego (US)
- Army Medical University (CN)
- Cleveland Clinic Lerner College of Medicine (US)
- Case Western Reserve University (US)
- Cleveland Clinic Research (US)
- Danish Cancer Society (DK)
- Baylor College of Medicine (US)
- Corresponding author
- Rich, Jeremy N.
- ORCID
- Wang, Xiuxing
- Prager, Briana C.
- Wu, Qiulian
- Kim, Leo J.Y.
- Gimple, Ryan C.
- Shi, Yu
- Yang, Kailin
- Morton, Andrew R.
- Zhou, Wenchao
- Zhu, Zhe
- Miller, Tyler E.
- Song, Anne
- Lai, Sisi
- Hubert, Christopher G.
- Jin, Xun
- Huang, Zhi
- Fang, Xiaoguang
- Dixit, Deobrat
- Tao, Weiwei
- Zhai, Kui
- Chen, Cong
- Dong, Zhen
- Zhang, Guoxin
- Dombrowski, Stephen M.
- Hamerlik, Petra
- Mack, Stephen C.
- Bao, Shideng
- Rich, Jeremy N.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 22
- Issue
- 4
- Pages
- 514-528.e5
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC5947947
- OpenAlex
- W2796407886
- Cited by
- 285
- References
- 74
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 54 · 2023: 42 · 2022: 25 · 2021: 40 · 2020: 31 · 2019: 30 · 2018: 14
- FWCI
- 16.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA197718, CA154130, CA169117, CA171652, NS087913, NS089272, CA184090, NS091080, NS099175)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- glioblastoma, glioblastoma stem cells, tumor microenvironment, brain-derived neurotrophic factor, NTRK2, VGF, paracrine signaling, tumor progression, stemness, tumor growth, patient-derived tumor models, epigenetic profiles
- MeSH terms
- Brain Neoplasms, Cell Differentiation, Glioblastoma, Humans, Neoplastic Stem Cells, Signal Transduction, Disease Progression
About these checks
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