Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling
Lawlor, K.; Marques-Torrejon, M. A.; Dharmalingham, G.; El-Azhar, Y.; Schneider, M. D.; Pollard, S. M.; Rodriguez, T.
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There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of hyperplasia are not easy to explore, but likely involve a cross-talk between normal and transformed NSCs. How normal cells respond to this cross-talk and if they expand or are outcompeted is poorly understood. Here we have analysed the interaction of transformed and wild-type NSCs isolated from the adult mouse subventricular zone neural stem cell niche. We find that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, however, we also demonstrate that these cells induce a quiescent-like state in surrounding wild-type NSC. We find that this response is cell-cell contact-dependent and that transformed cells activate the Notch pathway in adjacent wild-type NSCs, an event that stimulates their entry into quiescence. Our findings therefore suggest that oncogenic mutations may be propagated in the stem cell niche not just though cell-intrinsic advantages, but also by outcompeting neighbouring stem cells through signalling repression of their proliferation.
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