Intratumoral Crosstalk between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression

Glioblastoma is the most prevalent and lethal primary brain tumor, containing glioblastoma stem cells (GSCs) that initiate tumors and contribute to therapeutic resistance. GSCs reside in supportive microenvironments that provide critical maintenance cues; upon exiting their niches, GSCs lose self-renewal and undergo differentiation. Here, we interrogated the role of reciprocal signaling between GSCs and their differentiated progeny, differentiated glioblastoma cells (DGCs). Combining DGCs and GSCs accelerated tumor growth compared to growth of GSCs alone. Profiling matched GSCs and DGCs revealed preferential expression of brain-derived neurotrophic factor (BDNF) in DGCs, whereas GSCs expressed the cognate BDNF receptor, NTRK2. Forced expression of BDNF in DGCs augmented tumor growth when co-implanted with GSCs. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, and revealed preferential expression of the neurotrophic factor, VGF, by GSCs, which we confirmed in patient-derived tumor models. The BDNF-NTRK2 axis induced VGF expression through AKT activity. In turn, 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 a BDNF-NTRK2-VGF paracrine signaling loop to promote tumor growth.