Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth

Baoli Hu, Qianghu Wang, Y. Alan Wang, Sujun Hua, Charles Etienne Gabriel Sauvé, Derrick Ong, Zheng D. Lan, Qing Chang, Yan Wing Ho, Marta Moreno Monasterio, Xin Lu, Yi Zhong, Jianhua Zhang, Pingna Deng, Zhi Tan, Guocan Wang, Wen Ting Liao, Lynda J. Corley, Haiyan Yan, Junxia ZhangYongping You, Ning Liu, Linbo Cai, Gaetano Finocchiaro, Joanna J. Phillips, Mitchel S. Berger, Denise J. Spring, Jian Hu, Erik P. Sulman, Gregory N. Fuller, Lynda Chin, Roeland G W Verhaak, Ronald A. DePinho

Research output: Contribution to journalArticle

Abstract

Glioblastoma stem cells (GSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. To illuminate mechanisms governing these hallmark features, we developed a de novo glioblastoma multiforme (GBM) model derived from immortalized human neural stem/progenitor cells (hNSCs) to enable precise system-level comparisons of pre-malignant and oncogene-induced malignant states of NSCs. Integrated transcriptomic and epigenomic analyses uncovered a PAX6/DLX5 transcriptional program driving WNT5A-mediated GSC differentiation into endothelial-like cells (GdECs). GdECs recruit existing endothelial cells to promote peritumoral satellite lesions, which serve as a niche supporting the growth of invasive glioma cells away from the primary tumor. Clinical data reveal higher WNT5A and GdECs expression in peritumoral and recurrent GBMs relative to matched intratumoral and primary GBMs, respectively, supporting WNT5A-mediated GSC differentiation and invasive growth in disease recurrence. Thus, the PAX6/DLX5-WNT5A axis governs the diffuse spread of glioma cells throughout the brain parenchyma, contributing to the lethality of GBM.

Original languageEnglish
Pages (from-to)1281-1295.e18
JournalCell
Volume167
Issue number5
DOIs
Publication statusPublished - Nov 17 2016

Keywords

  • cancer stem cell differentiation
  • glioblastoma
  • recurrence
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hu, B., Wang, Q., Wang, Y. A., Hua, S., Sauvé, C. E. G., Ong, D., Lan, Z. D., Chang, Q., Ho, Y. W., Monasterio, M. M., Lu, X., Zhong, Y., Zhang, J., Deng, P., Tan, Z., Wang, G., Liao, W. T., Corley, L. J., Yan, H., ... DePinho, R. A. (2016). Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth. Cell, 167(5), 1281-1295.e18. https://doi.org/10.1016/j.cell.2016.10.039