![]() However, improved understanding of lineage progression is central to our understanding of the disease and may reveal novel strategies to suppress GBM growth and recurrence by directing GSC fate towards a mature, non-dividing state. In contrast, little is known about the differentiation potential of GSCs within tumours and whether pro-differentiative niches exist. Similarly, it is well established that GSCs are maintained in perivascular and hypoxic regions of the tumour bulk 12, 13, 14. Fate decisions of normal neural stem cells are tightly controlled by the microenvironment, which maintains stemness in specialised niches and directs differentiation along the appropriate lineages 11. Mounting evidence indicates that GSCs fuel tumourigenesis by recapitulating normal neural lineage hierarchies of quiescence, self-renewal and generation of non-dividing progeny 8, 9, 10. GBM initiation, growth and recurrence are thought to be rooted within a subpopulation of therapy-resistant tumour cells with properties of normal neural stem cells, termed glioma stem cells (GSCs) 3, 4, 5, 6, 7. Stark resistance to current treatments, which include maximal surgical resection, chemo- and radiotherapy, leads to tumour relapse in virtually all patients with a median survival of less than 15 months 2. Glioblastoma (GBM) is the most common and malignant primary brain tumour 1. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. ![]() Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. ![]()
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