期刊
CELL STEM CELL
卷 22, 期 4, 页码 514-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2018.03.011
关键词
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资金
- NIH [CA197718, CA154130, CA169117, CA171652, NS087913, NS089272, CA184090, NS091080, NS099175]
- NATIONAL CANCER INSTITUTE [F30CA217066, R35CA197718, R01CA171652, R01CA129958, F30CA217065, R01CA154130, R01CA169117, R01CA184090, R01CA116659] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [TL1TR000441] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007250] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS087913, K02NS047409, R01NS089272, R01NS091080, R01NS099175] Funding Source: NIH RePORTER
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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