SOX9 defines distinct populations of cells in SHH medulloblastoma but is not required for Math1-driven tumour formation
- Adolphe, C; Millar, A; Kojic, M; Barkauskas, DS; Sundstrom, A; Swartling, FJ; Hediyeh-Zadeh, S; Tan, CW; Davis, MJ; Genovesi, LA; Wainwright, BJ;
- 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
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2021-08-16 10:40:32Last Modified: 2021-08-16 10:43:54