Abstract 978: QKI deletion enhances self-renewal of glioma stem cells and promotes gliomagenesis

Author(s):  
Takashi Shingu ◽  
Allen Ho ◽  
Liang Yuan ◽  
Jian Hu
2020 ◽  
Vol 34 (4) ◽  
pp. 5128-5143
Author(s):  
Lilei Peng ◽  
Yang Ming ◽  
Ling Zhang ◽  
Jie Zhou ◽  
Wei Xiang ◽  
...  

2021 ◽  
Author(s):  
Zhi Huang ◽  
Kui Zhai ◽  
Qiulian Wu ◽  
Xiaoguang Fang ◽  
Qian Huang ◽  
...  

Glioblastoma (GBM) is the most lethal brain tumor containing glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance. The self-renewal and tumorigenic potential of GSCs are maintained by core stem cell transcription factors including SOX2. Defining the posttranslational regulation of SOX2 may offer new insights into GSC biology and potential therapeutic opportunity. Here, we discover that HAUSP stabilizes SOX2 through deubiquitination to maintain GSC self-renewal and tumorigenic potential. HAUSP is preferentially expressed in GSCs in perivascular niches in GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted SOX2 degradation, induced GSC differentiation, impaired GSC tumorigenic potential, and suppressed GBM tumor growth. Importantly, pharmacological inhibition of HAUSP synergized with radiation to inhibit GBM growth and extended animal survival, indicating that targeting HAUSP may overcome GSC-mediated radioresistance. Our findings reveal an unappreciated crucial role of HAUSP in the GSC maintenance and provide a promising target for developing effective anti-GSC therapeutics to improve GBM treatment.


BMC Cancer ◽  
2013 ◽  
Vol 13 (1) ◽  
Author(s):  
Jianhong Zhu ◽  
Handong Wang ◽  
Qing Sun ◽  
Xiangjun Ji ◽  
Lin Zhu ◽  
...  

2020 ◽  
Author(s):  
Gladiola Goranci-Buzhala ◽  
Aruljothi Mariappan ◽  
Lucia Ricci-Vitiani ◽  
Natasa Josipovic ◽  
Simone Pacion ◽  
...  

Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. GBM has a poor prognosis, and currently, there are no curative options exist. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of the fundamental biology of GSCs is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit an elevated level of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components at the ciliary base is sufficient to induce ciliogenesis in a subset of GSCs. Importantly, restoring ciliogenesis caused GSCs to behave like healthy NPCs switching from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a crucial role for cilium as a molecular switch in determining GSCs’ fate and suggest that cilium induction is an attractive strategy to intervene in GSCs proliferation.


PLoS Biology ◽  
2015 ◽  
Vol 13 (5) ◽  
pp. e1002152 ◽  
Author(s):  
Jinlong Yin ◽  
Gunwoo Park ◽  
Tae Hoon Kim ◽  
Jun Hee Hong ◽  
Youn-Jae Kim ◽  
...  

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jianhong Zhu ◽  
Handong Wang ◽  
Qing Sun ◽  
Xiangjun Ji ◽  
Lin Zhu ◽  
...  

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v86-v87
Author(s):  
H. K. Lee ◽  
E. Buchris ◽  
S. Finniss ◽  
S. Cazacu ◽  
C. Xiang ◽  
...  

Neoplasma ◽  
2014 ◽  
Vol 61 (04) ◽  
pp. 401-410 ◽  
Author(s):  
X. Y. ZHU ◽  
L. WANG ◽  
S. H. LUAN ◽  
H. S. ZHANG ◽  
W. T. HUANG ◽  
...  

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi235-vi236
Author(s):  
Alankrita Raghavan ◽  
Christine Lee-Poturalski ◽  
John Willis ◽  
Amber Kerstetter-Fogle ◽  
Peggy Harris ◽  
...  

Abstract Glioblastoma Multiforme (GBM) is the most common and lethal malignant primary adult brain tumor. Therapy resistance and tumor recurrence in GBM have been attributed to glioma stem cells (GSCs), which are found in hypoxic but perivascular niches. We hypothesized that the clinically documented and prognostically relevant increase in platelets in GBM promotes formation of functional hypoxic but perivascular niches that support GSCs due to formation of intravascular thromboses, a hallmark of GBM. Our preliminary in silico analysis from TCGA GBM samples indicates significant correlation of platelet and stemness signature expression (P < 0.001). High expression of platelet gene signatures also inversely correlates with overall survival in GBM patients (P < 0.02). Furthermore, we found significant co-localization of known platelet and stemness markers in primary GBM specimens, supporting our hypothesis and motivating further interrogation of GSC-platelet crosstalk. Our preliminary data suggest that GSCs exposed to either tumor or healthy platelets demonstrate increased self-renewal and stemness, as determined by a significant increase in OCT4, NANOG, and OLIG2 expression compared to unexposed GSCs. This increase in stemness and self-renewal markers was not seen in platelet-exposed differentiated glioma cell (DGC) counterparts. Conversely, platelets are stimulated by GSCs and GSC-conditioned media while DGCs elicit no stimulatory effects as measured by ATP release and aggregation assays. Our results implicate a functional role for platelet-GSC interactions in the maintenance of tumor cellular hierarchy that ultimately contributes to poor clinical outcomes in GBM. RNA-Seq of platelet-privileged GSCs is currently underway to elucidate the mechanism by which platelets impact GSC self-renewal. Successful characterization of potential crosstalk between platelets and GSCs may offer new clinical perspectives into GBM and inform development of a novel treatment paradigm to target these specific cell-to-cell interactions.


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