Reciprocal paracrine signaling between GBM stem cells and GBM cells promotes tumor growth.

  • Major finding: Reciprocal paracrine signaling between GBM stem cells and GBM cells promotes tumor growth.

  • Mechanism: BDNF–NTRK2 paracrine signaling induces GBM stem cell–derived VGF to promote GBM survival.

  • Impact: Combined inhibition of NTRK2 and PI3K–AKT signaling is a potential therapeutic strategy to target GSCs.

Glioblastoma (GBM) is the most common adult brain malignancy and exhibits significant cellular hierarchies driven by GBM stem cells (GSC), the radio- and chemoresistant CD133+ stem-like cell subpopulation of GBMs which reside in and are supported by vascular and hypoxic GSC niches. However, it is unclear whether differentiated GBM cells (DGC) contribute to GSC growth in GBM cellular hierarchies; thus, Wang and colleagues generated matched GSCs and DGCs from patient-derived GBM neurosphere cultures and performed flank and orthotopic implantations of mice with GSCs, DGCs, GSCs and DGCs, or GSCs and fibroblasts. Intracranial implantations of GSCs and DGCs, and not GSCs alone or GSCs and fibroblasts, recapitulated the growth kinetics of bulk unsorted GBM neurosphere cultures. Compared to GSCs, DGCs were shown to secrete high levels of the neuronal growth factor BDNF, and differentiation of GSCs promoted increased BDNF mRNA expression and secretion; further, it was shown that expression of the BDNF receptor NTRK2 was upregulated in GSCs. Consistent with these findings, immunofluorescent staining of patient samples showed NTRK2 was specifically expressed by tumor cells that were positive for the GSC marker SOX2. Orthotopic implantation of mixed BDNF-depleted DGCs and GSCs resulted in reduced tumor growth compared with that of BDNF-expressing DGCs and GSCs, and GSCs transduced with BDNF exhibited greater intracranial tumor growth and poorer survival outcome than untransduced GSCs. BDNF induced the upregulation of VGF specifically in GSCs via activated PI3K–AKT signaling, and VGF was shown to be critical for GSC growth and stemness. Moreover, VGF promoted increased DGC viability and growth, and mice intracranially implanted with VGF-depleted GSCs exhibited increased survival and an absence of tumors. These findings demonstrate how tumor stem cell–differentiated tumor cell interactions determine GBM hierarchical growth and identify potential therapeutic strategies that may target GSCs.

Wang X, Prager BC, Wu Q, Kim LJ, Gimple RC, Shi Y, et al. Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell Stem Cell 2018;22:514–28.

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