SOX9+ malignant cells define a poor prognosis subtype of Glioma with tumor-associated macrophage recruitment

Abstract Background Gliomas, as the most common aggressive type of primary brain tumors, are highly prevalent and incurable among adults. The dysregulation of transcription factors, including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) genes, are considered to be important in cancer development and progression. The aim of our study was to evaluate the effect of SOX9 in the prognosis of glioma. Results We revealed aberrant regulation of most SOX family genes by using 1289 glioma samples from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts. We identified 4 critical genes, SOX3, SOX6, SOX8 and SOX9, -based risk signature model through LASSO regression and a specific SOX9 + cell state with more pronounced malignancy through high-quality single-cell RNA sequencing data analysis. The up regulation of SOX9 and the downregulation of SOX3, SOX6, and SOX8 indicate a decrease in overall survival. The SOX9 + cell state represents a greater proliferative capacity and invasive metastatic properties and is a primary source of attraction for infiltration of bone marrow-derived myeloid (BMM) cells, which are also demonstrated by multicolor immunofluorescence analysis. Conclusions Our study suggests that SOX9 is an independent prognostic and predictive factor for glioma, and the potential interaction between SOX9 + malignant cells and BMM deserves further investigation.