Association of glioma CD44 expression with glial dynamics in the tumour microenvironment and patient prognosis

Zhanxin Du; Yaqing Wang; Jiaqi Liang; Shaowei Gao; Xiaoying Cai; Yu Yu; Zhihui Qi; Jing Li; Yubin Xie; Zhongxing Wang

doi:10.1016/j.csbj.2022.09.003

Association of glioma CD44 expression with glial dynamics in the tumour microenvironment and patient prognosis

Comput Struct Biotechnol J. 2022 Sep 9:20:5203-5217. doi: 10.1016/j.csbj.2022.09.003. eCollection 2022.

Authors

Zhanxin Du¹, Yaqing Wang¹, Jiaqi Liang², Shaowei Gao¹, Xiaoying Cai¹, Yu Yu¹, Zhihui Qi¹, Jing Li¹, Yubin Xie³, Zhongxing Wang¹

Affiliations

¹ Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, PR China.
² School of Life Sciences, Sun Yat-sen University, No. 135 Xingangxi Road, Guangzhou 510275, PR China.
³ Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, PR China.

Abstract

Because of the heterogeneity of lower-grade gliomas (LGGs), patients show various survival outcomes that are not reliably predicted by histological classification. The tumour microenvironment (TME) contributes to the initiation and progression of brain LGGs. Identifying potential prognostic markers based on the immune and stromal components in the TME will provide new insights into the dynamic modulation of these two components of the TME in LGGs. We applied ESTIMATE to calculate the ratio of immune and stromal components from The Cancer Genome Atlas database. After combined differential gene expression analysis, protein-protein interaction network construction and survival analysis, CD44 was screened as an independent prognostic factor and subsequently validated utilizing data from the Chinese Glioma Genome Atlas database. To decipher the association of glioma cell CD44 expression with stromal cells in the TME and tumour progression, RT-qPCR, cell viability and wound healing assays were employed to determine whether astrocytes enhance glioma cell viability and migration by upregulating CD44 expression. Surprisingly, M1 macrophages were identified as positively correlated with CD44 expression by CIBERSORT analysis. CD44⁺ glioma cells were further suggested to interact with microglia-derived macrophages (M1 phenotype) via osteopontin signalling on the basis of single-cell sequencing data. Overall, we found that astrocytes could elevate the CD44 expression level of glioma cells, enhancing the recruitment of M1 macrophages that may promote glioma stemness via osteopontin-CD44 signalling. Thus, glioma CD44 expression might coordinate with glial activities in the TME and serve as a potential therapeutic target and prognostic marker for LGGs.

Keywords: ACM, Astrocyte-conditioned medium; BBB, Blood–brain barrier; CD44; CGGA, The Chinese Glioma Genome Atlas; CSCs, Cancer stem cells; GBM, Glioblastoma; GSCs, Glioma stem cells; Glial cells; LGGs, Lower-grade gliomas; Lower-grade gliomas; OPN, Osteopontin; OS, Overall survival; PDL, Poly-d-lysine; Prognosis; RT-qPCR, Real-time quantitative polymerase chain reaction; SPP1, Secreted phosphoprotein 1; TAMs, Tumour-associated macrophages; TCGA, The Cancer Genome Atlas; TIC, Tumour-infiltrating immune cell; TME, Tumour microenvironment; Tumour microenvironment.