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.
Original language | English (US) |
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Pages (from-to) | 75-86 |
Number of pages | 12 |
Journal | Nature Genetics |
Volume | 49 |
Issue number | 1 |
DOIs | |
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