SOX9 defines distinct populations of cells in SHH medulloblastoma but is not required for Math1-driven tumour formation
Journal Title
Molecular Cancer Research
Publication Type
epub ahead of print
Medulloblastoma (MB) is the most common malignant pediatric brain tumour and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of MB remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCPs) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wildtype GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9low GCP-like tumour cells constitute the bulk of both infant (Math1Cre:Ptch1lox/lox) and adult (Ptch1LacZ/+) SHH-MB mouse models. Human MB single cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other MB subgroups: SOX9+MATH1+ (GCPs), SOX9+GFAP+ (astrocytes) and SOX9+MATH1+GFAP+ (potential tumour-derived astrocytes). In order to functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in MB tumour cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9lox/lox) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1lox/lox;Sox9lox/lox) does not affect tumour formation. Implications: Despite pre-clinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target.
WEHI Research Division(s)
PubMed ID
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Creation Date: 2021-08-16 10:40:32
Last Modified: 2021-08-16 10:43:54
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