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Cell Stem Cell. 2018 Apr 5;22(4):514-528.e5. doi: 10.1016/j.stem.2018.03.011.

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

Author information

1
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, USA.
2
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
3
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
4
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing, China.
5
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
6
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
7
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
8
Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen 2100, Denmark.
9
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
10
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
11
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, USA. Electronic address: drjeremyrich@gmail.com.

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.

KEYWORDS:

BDNF; NTRK2; VGF; cancer stem cell; differentiated glioma cell; glioblastoma; glioma stem cell; neurotrophin

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