A distinct perivascular niche has been implicated in many aspects of tumor biology, particularly stemness, invasion, survival, and therapy resistance of cancer cells. But its overall importance for these factors remains obscure.

By using multidimensional intravital imaging, that allows following individual glioblastoma cells in distinct brain microregions over long periods of time, we demonstrate that the perivascular niche plays a crucial role for many aspects of brain tumor progression. Glioblastoma stem-like cells (GBMSCs) colonized the perivascular niche in significant numbers, and used it as a route for effective brain invasion. This was partly explained by the fact that tumor microtubes (TMs), a novel cellular mechanism of glioblastoma progression and resistance (Osswald et al., Nature 2015), followed the perivascular room of the dense brain microcapillary network as a leading track. A subfraction of GBMSCs in a perivascular position showed long-term dormancy. Furthermore, location in the perivascular niche was associated with a high resistance against cytotoxic effects of radiotherapy, and with the ability of GBMSCs to repair damage inflicted to their tumor microregion. Proficient NOTCH1 expression was required for successful perivascular niche colonization, and NOTCH1 deficiency reduced the radioresistance of perivascular tumor cells. Double-positivity for perivascular niche position and TM-formation was associated with the strongest primary resistance to therapies, and the strongest damage repair competence of an individual tumor cell.

Taken together, these results provide the first direct evidence that a perivascular niche position is relevant for glioblastoma cells to exert central malignant traits, including those that have been associated with cancer stem-like cells. Targeting the subpopulation of glioma cells that colonizes the perivascular niche emerges as an important task for the development of novel therapies, since existing treatment modalities fall short of controlling these cells.