SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation.

Adolphe C, Millar A, Kojic M, Barkauskas DS, Sundström A, Swartling FJ, Hediyeh-Zadeh S, Tan CW, Davis MJ, Genovesi LA, Wainwright BJ

Mol. Cancer Res. 19 (11) 1831-1839 [2021-11-00; online 2021-07-30]

Medulloblastoma is the most common malignant pediatric brain tumor 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 medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9low GCP-like tumor cells constitute the bulk of both infant (Math1Cre:Ptch1 ) and adult (lox/loxPtch1 ) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct LacZ/+SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9 + MATH1 + (GCP), SOX9 + GFAP + (astrocytes) and SOX9 + MATH1 + GFAP + (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9 ) revealed no overt phenotype and loss of lox/loxSox9 in SHH-MB (Math1Cre:Ptch1 ) does not affect tumor formation. IMPLICATIONS: Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target.lox/lox;Sox9lox/lox

PubMed 34330843

DOI 10.1158/1541-7786.MCR-21-0117

Crossref 10.1158/1541-7786.MCR-21-0117

pii: 1541-7786.MCR-21-0117