Cited by 285Glioma Diagnosis and TreatmentCancer Cells and MetastasisNeurogenesis and neuroplasticity mechanisms

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

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Wang, Xiuxing, Prager, Briana C., Wu, Qiulian, Kim, Leo J.Y., Gimple, Ryan C., Shi, Yu, Yang, Kailin, Morton, Andrew R. +21 more·2018·Cell Stem Cell

Abstract

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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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.
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
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 · 2016: 1
FWCI
16.26
Type
journal article
Language
en
Open access
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 › Genetics › 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

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