CXCR4 expression is associated with proneural-to-mesenchymal transition in glioblastoma

A. Basit Khan, Sungho Lee, Akdes Serin Harmanci, Rajan Patel, Khatri Latha, Yuhui Yang, Anantha Marisetty, Hyun Kyoung Lee, Amy B. Heimberger, Gregory N. Fuller, Benjamin Deneen, Ganesh Rao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial-mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 signaling increases the expression of MES genes in glioma cell lines and promotes EMT in other cancers. RNA sequencing (RNAseq) data of PN GBMs in The Cancer Genome Atlas (TCGA) and secondary high-grade gliomas (HGGs) from an internal cohort were examined for correlation between CXCR4 expression and survival as well as expression of MES markers. Publicly available single-cell RNA sequencing (scRNAseq) data was analyzed for cell type specific CXCR4 expression. These results were validated in a genetic mouse model of PN GBM. Higher CXCR4 expression was associated with significantly reduced survival and increased expression of MES markers in TCGA and internal cohorts. CXCR4 was expressed in immune and tumor cells based on scRNAseq analysis. Higher CXCR4 expression within tumor cells on scRNAseq was associated with increased MES phenotype, suggesting a cell-autonomous effect. In a genetically engineered mouse model, tumors induced with CXCR4 exhibited a mesenchymal phenotype and shortened survival. These results suggest that CXCR4 signaling promotes PMT and shortens survival in GBM and highlights its inhibition as a potential therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)713-724
Number of pages12
JournalInternational Journal of Cancer
Volume152
Issue number4
DOIs
StatePublished - Feb 15 2023

Keywords

  • chemokine
  • glioblastoma
  • mesenchymal
  • proneural

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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