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

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

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190 Scopus citations

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 language	English (US)
Pages (from-to)	1281-1295.e18
Journal	Cell
Volume	167
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.10.039
State	Published - Nov 17 2016

Keywords

cancer stem cell differentiation
glioblastoma
recurrence
tumor microenvironment

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Bioinformatics Shared Resource
Flow Cytometry and Cellular Imaging Facility
Research Animal Support Facility
Small Animal Imaging Facility
Cytogenetics and Cell Authentication Core

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10.1016/j.cell.2016.10.039

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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

Hu, B, Wang, Q, Wang, YA, Hua, S, Sauvé, CEG, Ong, D, Lan, ZD, Chang, Q, Ho, YW, Monasterio, MM, Lu, X, Zhong, Y, Zhang, J, Deng, P, Tan, Z, Wang, G, Liao, WT, Corley, LJ, Yan, H, Zhang, J, You, Y, Liu, N, Cai, L, Finocchiaro, G, Phillips, JJ, Berger, MS, Spring, DJ, Hu, J, Sulman, EP, Fuller, GN, Chin, L, Verhaak, RGW & DePinho, RA 2016, 'Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth', Cell, vol. 167, no. 5, pp. 1281-1295.e18. https://doi.org/10.1016/j.cell.2016.10.039

@article{36c2f5d0f0db4d29a13bff66a793c89c,

title = "Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth",

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",

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

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = nov,

day = "17",

doi = "10.1016/j.cell.2016.10.039",

language = "English (US)",

volume = "167",

pages = "1281--1295.e18",

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T1 - Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth

AU - Hu, Baoli

AU - Wang, Qianghu

AU - Wang, Y. Alan

AU - Hua, Sujun

AU - Sauvé, Charles Etienne Gabriel

AU - Ong, Derrick

AU - Lan, Zheng D.

AU - Chang, Qing

AU - Ho, Yan Wing

AU - Monasterio, Marta Moreno

AU - Lu, Xin

AU - Zhong, Yi

AU - Zhang, Jianhua

AU - Deng, Pingna

AU - Tan, Zhi

AU - Wang, Guocan

AU - Liao, Wen Ting

AU - Corley, Lynda J.

AU - Yan, Haiyan

AU - Zhang, Junxia

AU - You, Yongping

AU - Liu, Ning

AU - Cai, Linbo

AU - Finocchiaro, Gaetano

AU - Phillips, Joanna J.

AU - Berger, Mitchel S.

AU - Spring, Denise J.

AU - Hu, Jian

AU - Sulman, Erik P.

AU - Fuller, Gregory N.

AU - Chin, Lynda

AU - Verhaak, Roeland G.W.

AU - DePinho, Ronald A.

PY - 2016/11/17

Y1 - 2016/11/17

N2 - 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.

AB - 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.

KW - cancer stem cell differentiation

KW - glioblastoma

KW - recurrence

KW - tumor microenvironment

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U2 - 10.1016/j.cell.2016.10.039

DO - 10.1016/j.cell.2016.10.039

M3 - Article

C2 - 27863244

AN - SCOPUS:84995893096

SN - 0092-8674

VL - 167

SP - 1281-1295.e18

JO - Cell

JF - Cell

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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