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 Zhang; Yongping 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

doi:10.1016/j.cell.2016.10.039

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

Cell. 2016 Nov 17;167(5):1281-1295.e18. doi: 10.1016/j.cell.2016.10.039.

Authors

Baoli Hu¹, Qianghu Wang², Y Alan Wang³, Sujun Hua¹, Charles-Etienne Gabriel Sauvé¹, Derrick Ong¹, Zheng D Lan¹, Qing Chang⁴, Yan Wing Ho¹, Marta Moreno Monasterio¹, Xin Lu¹, Yi Zhong⁵, Jianhua Zhang⁴, Pingna Deng¹, Zhi Tan⁶, Guocan Wang¹, Wen-Ting Liao¹, Lynda J Corley⁷, Haiyan Yan⁸, Junxia Zhang⁹, Yongping You⁹, Ning Liu⁹, Linbo Cai¹⁰, Gaetano Finocchiaro¹¹, Joanna J Phillips¹², Mitchel S Berger¹³, Denise J Spring¹, Jian Hu¹, Erik P Sulman¹⁴, Gregory N Fuller⁷, Lynda Chin¹⁵, Roeland G W Verhaak², Ronald A DePinho¹⁶

Affiliations

¹ Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org.
⁴ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
¹⁰ Department of Oncology, Guangdong 999 Brain Hospital, Guangzhou 510510, China.
¹¹ Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milano, Italy.
¹² Departments of Neurological Surgery and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹³ Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁵ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁶ Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.

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.

Keywords: cancer stem cell differentiation; glioblastoma; recurrence; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Endothelial Cells / cytology
Endothelial Cells / metabolism
Epigenomics
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics*
Glioblastoma / pathology*
Homeodomain Proteins / metabolism
Humans
Neoplasm Invasiveness / genetics*
Neural Stem Cells / metabolism
PAX6 Transcription Factor / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Transcription Factors / metabolism
Wnt-5a Protein / genetics*

Substances

DLX5 protein, human
Homeodomain Proteins
PAX6 Transcription Factor
PAX6 protein, human
Transcription Factors
WNT5A protein, human
Wnt-5a Protein
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding