Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation

Takashi Shingu; Allen L. Ho; Liang Yuan; Xin Zhou; Congxin Dai; Siyuan Zheng; Qianghu Wang; Yi Zhong; Qing Chang; James W. Horner; Brandon D. Liebelt; Yu Yao; Baoli Hu; Yiwen Chen; Gregory N. Fuller; Roeland G.W. Verhaak; Amy B. Heimberger; Jian Hu

doi:10.1038/ng.3711

Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation

Takashi Shingu, Allen L. Ho, Liang Yuan, Xin Zhou, Congxin Dai, Siyuan Zheng, Qianghu Wang, Yi Zhong, Qing Chang, James W. Horner, Brandon D. Liebelt, Yu Yao, Baoli Hu, Yiwen Chen, Gregory N. Fuller, Roeland G.W. Verhaak, Amy B. Heimberger, Jian Hu^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten^-/-; Trp53^-/- background helps NSCs maintain their stemness outside the SVZ in Nes-CreER^T2; Qk^L/L; Pten^L/L; Trp53^L/L mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.

Original language	English (US)
Pages (from-to)	75-86
Number of pages	12
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3711
State	Published - Jan 1 2017

Funding

J.H. is supported by an NIH K99/R00 Pathway to Independence Award (R00 CA172700), a University of Texas Rising STARs award, an NCI Brain Cancer SPORE Career Development Award (2P50CA127001), and a Sidney Kimmel Scholar Award. A.L.H. was supported by the HHMI Medical Research Fellows Program. A.B.H. is supported by NIH R01 CA120813. Y.C. is supported by NCI R00CA175290 and Texas CPRIT grant RR140071.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng.3711

Cite this

Shingu, T., Ho, A. L., Yuan, L., Zhou, X., Dai, C., Zheng, S., Wang, Q., Zhong, Y., Chang, Q., Horner, J. W., Liebelt, B. D., Yao, Y., Hu, B., Chen, Y., Fuller, G. N., Verhaak, R. G. W., Heimberger, A. B., & Hu, J. (2017). Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation. Nature Genetics, 49(1), 75-86. https://doi.org/10.1038/ng.3711

@article{a55edba503014f088bc742be28d8bca8,

title = "Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation",

abstract = "Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten-/-; Trp53-/- background helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2; QkL/L; PtenL/L; Trp53L/L mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.",

author = "Takashi Shingu and Ho, {Allen L.} and Liang Yuan and Xin Zhou and Congxin Dai and Siyuan Zheng and Qianghu Wang and Yi Zhong and Qing Chang and Horner, {James W.} and Liebelt, {Brandon D.} and Yu Yao and Baoli Hu and Yiwen Chen and Fuller, {Gregory N.} and Verhaak, {Roeland G.W.} and Heimberger, {Amy B.} and Jian Hu",

year = "2017",

month = jan,

day = "1",

doi = "10.1038/ng.3711",

language = "English (US)",

volume = "49",

pages = "75--86",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

Shingu, T, Ho, AL, Yuan, L, Zhou, X, Dai, C, Zheng, S, Wang, Q, Zhong, Y, Chang, Q, Horner, JW, Liebelt, BD, Yao, Y, Hu, B, Chen, Y, Fuller, GN, Verhaak, RGW, Heimberger, AB & Hu, J 2017, 'Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation', Nature Genetics, vol. 49, no. 1, pp. 75-86. https://doi.org/10.1038/ng.3711

TY - JOUR

T1 - Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation

AU - Shingu, Takashi

AU - Ho, Allen L.

AU - Yuan, Liang

AU - Zhou, Xin

AU - Dai, Congxin

AU - Zheng, Siyuan

AU - Wang, Qianghu

AU - Zhong, Yi

AU - Chang, Qing

AU - Horner, James W.

AU - Liebelt, Brandon D.

AU - Yao, Yu

AU - Hu, Baoli

AU - Chen, Yiwen

AU - Fuller, Gregory N.

AU - Verhaak, Roeland G.W.

AU - Heimberger, Amy B.

AU - Hu, Jian

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten-/-; Trp53-/- background helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2; QkL/L; PtenL/L; Trp53L/L mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.

AB - Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten-/-; Trp53-/- background helps NSCs maintain their stemness outside the SVZ in Nes-CreERT2; QkL/L; PtenL/L; Trp53L/L mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.

UR - http://www.scopus.com/inward/record.url?scp=84995426835&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995426835&partnerID=8YFLogxK

U2 - 10.1038/ng.3711

DO - 10.1038/ng.3711

M3 - Article

C2 - 27841882

AN - SCOPUS:84995426835

SN - 1061-4036

VL - 49

SP - 75

EP - 86

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this