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

被引：216

作者：

Hu, Baoli ^{[1
]}

Wang, Qianghu ^{[2
,3
]}

Wang, Y. Alan ^{[1
]}

Hua, Sujun ^{[1
]}

Sauve, Charles-Etienne Gabriel ^{[1
]}

Ong, Derrick ^{[1
]}

Lan, Zheng D. ^{[1
]}

Chang, Qing ^{[3
,9
]}

Ho, Yan Wing ^{[1
]}

Monasterio, Marta Moreno ^{[1
]}

Lu, Xin ^{[1
]}

Zhong, Yi ^{[4
]}

Zhang, Jianhua ^{[3
,9
]}

Deng, Pingna ^{[1
]}

Tan, Zhi ^{[5
]}

Wang, Guocan ^{[1
]}

Liao, Wen-Ting ^{[1
]}

Corley, Lynda J. ^{[6
]}

Yan, Haiyan ^{[10
]}

Zhang, Junxia ^{[11
]}

You, Yongping ^{[11
]}

Liu, Ning ^{[11
]}

Cai, Linbo ^{[12
]}

Finocchiaro, Gaetano ^{[13
]}

Phillips, Joanna J. ^{[14
]}

Berger, Mitchel S. ^{[15
]}

Spring, Denise J. ^{[1
]}

Hu, Jian ^{[1
]}

Sulman, Erik P. ^{[7
,8
]}

Fuller, Gregory N. ^{[6
]}

Chin, Lynda ^{[3
]}

Verhaak, Roeland G. W. ^{[2
,3
]}

DePinho, Ronald A. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[10] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[11] Nanjing Med Univ, Dept Neurosurg, Affiliated Hosp 1, Nanjing 210029, Jiangsu, Peoples R China

[12] Guangdong 999 Brain Hosp, Dept Oncol, Guangzhou 510510, Guangdong, Peoples R China

[13] Fdn IRCCS Ist Neurol C Besta, Unit Mol Neurooncol, I-20133 Milan, Italy

[14] Univ Calif San Francisco, Dept Neurol Surg & Pathol, San Francisco, CA 94143 USA

[15] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

来源：

CELL | 2016年 / 167卷 / 05期

关键词：

ENDOTHELIAL-CELLS; SELF-RENEWAL; MALIGNANT GLIOMAS; PAX6; SUPPRESSES; IN-VITRO; CANCER; EXPRESSION; PROLIFERATION; DYNAMICS; NEUROGENESIS;

D O I：

10.1016/j.cell.2016.10.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1281 / +

页数：32

共 50 条

[1] Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice [J].

Adam, Rene C. ;

Yang, Hanseul ;

Rockowitz, Shira ;

Larsen, Samantha B. ;

Nikolova, Maria ;

Oristian, Daniel S. ;

Polak, Lisa ;

Kadaja, Meelis ;

Asare, Amma ;

Zheng, Deyou ;

Fuchs, Elaine .

NATURE, 2015, 521 (7552) :366-+

[2] Glioma stem cells promote radioresistance by preferential activation of the DNA damage response [J].

Bao, Shideng ;

Wu, Qiulian ;

McLendon, Roger E. ;

Hao, Yueling ;

Shi, Qing ;

Hjelmeland, Anita B. ;

Dewhirst, Mark W. ;

Bigner, Darell D. ;

Rich, Jeremy N. .

NATURE, 2006, 444 (7120) :756-760

[3] A bivalent chromatin structure marks key developmental genes in embryonic stem cells [J].

Bernstein, BE ;

Mikkelsen, TS ;

Xie, XH ;

Kamal, M ;

Huebert, DJ ;

Cuff, J ;

Fry, B ;

Meissner, A ;

Wernig, M ;

Plath, K ;

Jaenisch, R ;

Wagschal, A ;

Feil, R ;

Schreiber, SL ;

Lander, ES .

CELL, 2006, 125 (02) :315-326

[4] Recruitment of bone marrow derived cells during anti-angiogenic therapy in GBM: The potential of combination strategies [J].

Boer, Jennifer C. ;

Walenkamp, Annemiek M. E. ;

den Dunnen, Wilfred F. A. .

CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2014, 92 (01) :38-48

[5] The Somatic Genomic Landscape of Glioblastoma [J].

Brennan, Cameron W. ;

Verhaak, Roel G. W. ;

McKenna, Aaron ;

Campos, Benito ;

Noushmehr, Houtan ;

Salama, Sofie R. ;

Zheng, Siyuan ;

Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

Bernard, Brady ;

Wu, Chang-Jiun ;

Genovese, Giannicola ;

Shmulevich, Ilya ;

Barnholtz-Sloan, Jill ;

Zou, Lihua ;

Vegesna, Rahulsimham ;

Shukla, Sachet A. ;

Ciriello, Giovanni ;

Yung, W. K. ;

Zhang, Wei ;

Sougnez, Carrie ;

Mikkelsen, Tom ;

Aldape, Kenneth ;

Bigner, Darell D. ;

Van Meir, Erwin G. ;

Prados, Michael ;

Sloan, Andrew ;

Black, Keith L. ;

Eschbacher, Jennifer ;

Finocchiaro, Gaetano ;

Friedman, William ;

Andrews, David W. ;

Guha, Abhijit ;

Iacocca, Mary ;

O'Neill, Brian P. ;

Foltz, Greg ;

Myers, Jerome ;

Weisenberger, Daniel J. ;

Penny, Robert ;

Kucherlapati, Raju ;

Perou, Charles M. ;

Hayes, D. Neil ;

Gibbs, Richard ;

Marra, Marco ;

Mills, Gordon B. ;

Lander, Eric ;

Spellman, Paul ;

Wilson, Richard .

CELL, 2013, 155 (02) :462-477

[6] A perivascular niche for brain tumor stem cells [J].

Calabrese, Christopher ;

Poppleton, Helen ;

Kocak, Mehmet ;

Hogg, Twala L. ;

Fuller, Christine ;

Hamner, Blair ;

Oh, Eun Young ;

Gaber, M. Waleed ;

Finklestein, David ;

Allen, Meredith ;

Frank, Adrian ;

Bayazitov, Ildar T. ;

Zakharenko, Stanislav S. ;

Gajjar, Amar ;

Davidoff, Andrew ;

Gilbertson, Richard J. .

CANCER CELL, 2007, 11 (01) :69-82

[7] Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma [J].

Ceccarelli, Michele ;

Barthel, Floris P. ;

Malta, Tathiane M. ;

Sabedot, Thais S. ;

Salama, Sofie R. ;

Murray, Bradley A. ;

Morozova, Olena ;

Newton, Yulia ;

Radenbaugh, Amie ;

Pagnotta, Stefano M. ;

Anjum, Samreen ;

Wang, Jiguang ;

Manyam, Ganiraju ;

Zoppoli, Pietro ;

Ling, Shiyun ;

Rao, Arjun A. ;

Grifford, Mia ;

Cherniack, Andrew D. ;

Zhang, Hailei ;

Poisson, Laila ;

Carlotti, Carlos Gilberto, Jr. ;

Tirapelli, Daniela Pretti da Cunha ;

Rao, Arvind ;

Mikkelsen, Tom ;

Lau, Ching C. ;

Yung, W. K. Alfred ;

Rabadan, Raul ;

Huse, Jason ;

Brat, Daniel J. ;

Lehman, Norman L. ;

Barnholtz-Sloan, Jill S. ;

Zheng, Siyuan ;

Hess, Kenneth ;

Rao, Ganesh ;

Meyerson, Matthew ;

Beroukhim, Rameen ;

Cooper, Lee ;

Akbani, Rehan ;

Wrensch, Margaret ;

Haussler, David ;

Aldape, Kenneth D. ;

Laird, Peter W. ;

Gutmann, David H. ;

Noushmehr, Houtan ;

Iavarone, Antonio ;

Verhaak, Roel G. W. .

CELL, 2016, 164 (03) :550-563

[8] A restricted cell population propagates glioblastoma growth after chemotherapy [J].

Chen, Jian ;

Li, Yanjiao ;

Yu, Tzong-Shiue ;

McKay, Renee M. ;

Burns, Dennis K. ;

Kernie, Steven G. ;

Parada, Luis F. .

NATURE, 2012, 488 (7412) :522-+

[9] Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration [J].

Cheng, Ching-wen ;

Yeh, Ju-ching ;

Fan, Tai-Ping ;

Smith, Stephen K. ;

Charnock-Jones, D. Stephen .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 365 (02) :285-290

[10] Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth [J].

Cheng, Lin ;

Huang, Zhi ;

Zhou, Wenchao ;

Wu, Qiulian ;

Donnola, Shannon ;

Liu, James K. ;

Fang, Xiaoguang ;

Sloan, Andrew E. ;

Mao, Yubin ;

Lathia, Justin D. ;

Min, Wang ;

McLendon, Roger E. ;

Rich, Jeremy N. ;

Bao, Shideng .

CELL, 2013, 153 (01) :139-152

← 1 2 3 4 5 →