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

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) con-tributes 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 modu-lation 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.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study identified CD44 as an independent prognostic factor for lower-grade gliomas (LGGs) by analyzing the ratio of immune and stromal components in the tumor microenvironment (TME). The research also revealed that astrocytes enhance the viability and migration of glioma cells by upregulating CD44 expression, and CD44 expression is positively correlated with M1 macrophages. These findings highlight the important role of CD44 in the TME and suggest it as a potential therapeutic target and prognostic marker for LGGs.