Loss-of-function screens of druggable targetome against cancer stem-like cells.
Cancer stem-like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.-Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem-like cells.
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.
Mee
M
Song
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
Hani
H
Lee
Environmental Risk and Welfare Research Team, Korea Basic Science Institute, Seoul, Korea.
Myung-Hee
MH
Nam
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.
Euna
E
Jeong
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.
Somin
S
Kim
Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea.
Yourae
Y
Hong
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.|Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea.
Nayoung
N
Kim
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.
Hwa Young
HY
Yim
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
Young-Ji
YJ
Yoo
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
Jung Seok
JS
Kim
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
Jin-Seok
JS
Kim
College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Korea; and.
Yong-Yeon
YY
Cho
Systems Biology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA.
Gordon B
GB
Mills
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea; wykim@sookmyung.ac.kr.
Woo-Young
WY
Kim
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea; yoonsj@sookmyung.ac.kr.|Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea.
Sukjoon
S
Yoon
D000818:Animals; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering
D034741:RNA, Small Interfering
CSLC sphere culture; lipid profile; network analysis; siRNA screening