TY - JOUR T1 - The white matter is a pro-differentiative microenvironment for glioblastoma JF - bioRxiv DO - 10.1101/2020.11.14.379594 SP - 2020.11.14.379594 AU - Lucy J. Brooks AU - Melanie P. Clements AU - Jemima J. Burden AU - Daniela Kocher AU - Luca Richards AU - Sara Castro Devesa AU - Megan Woodberry AU - Michael Ellis AU - Leila Zakka AU - Zane Jaunmuktane AU - Sebastian Brandner AU - Gillian Morrison AU - Steven M. Pollard AU - Peter B. Dirks AU - Samuel Marguerat AU - Simona Parrinello Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/16/2020.11.14.379594.abstract N2 - Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but how they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte-like fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to white matter-independent pre-oligodendrocyte-like differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.Competing Interest StatementThe authors have declared no competing interest. ER -