The white matter is a pro-differentiative niche for glioblastoma

Abstract

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or 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 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 niche-independent pre-oligodendrocyte 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.

Old Stars and New Players in the Brain Tumor Microenvironment

“…They found that CD133 + bona-fide glioma stem cells are preferentially associated with portions of nerve fibers, where myelin is lost and unconstrained axonal signals stimulate glioma cell survival. Partial demyelination nearby white matter infiltration was also recently reported by Brooks et al (2021). The authors described, in addition, axonal degeneration, OPCs recruitment and microglia activation: all events usually occurring in demyelinated lesions (Franklin and Ffrench-Constant, 2008).…”

“…The authors described, in addition, axonal degeneration, OPCs recruitment and microglia activation: all events usually occurring in demyelinated lesions (Franklin and Ffrench-Constant, 2008). Surprisingly, this white matter injured-like microenvironment is sufficient to stop proliferation of infiltrating tumor cells and to upregulated SOX10 which induces differentiation of tumor cells toward the oligodendrocyte lineage (Brooks et al, 2021). Therefore, in white matter tracts tumor cells may encounter opposite signals stimulating stemness or differentiation.…”

Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells

“…To determine whether diet could also impact oncogenic transformation, we examined effects of fish oil supplementation on tumour initiation from NSCs in a somatic mouse model of GBM based on CRISPR/Cas9 gene editing and PiggyBac transposition technology (Zuckermann et al ., 2015; Brooks et al ., 2021; Garcia-Diaz et al ., 2021). The model is driven by combined inactivation of the tumour suppressor genes Nf1, Pten and Trp53 (hereon NPP model) in endogenous postnatal SVZ NSCs and includes stable integration of a tdTomato reporter gene in all tumour cells (Figure S4A).…”

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management

“…Molecules at the level of this myelin sheath may inhibit glioma cell migration and proliferation ( 46 , 57 ). WM is a pro-differentiative niche for glioblastomas, since glioma cells in contact with WM can acquire pre-oligodendrocyte fate, leading to a decreased proliferation and invasion ( 58 ). However, the neoplasm itself may damage WM, especially by secreting mettaloproteinases able to overcome the inhibitory effect of myelin and to create suitable conditions for tumor cell invasion ( 59 ).…”