TY  - JOUR
AU  - Huang, Yulun
AU  - Qi, Lin
AU  - Kogiso, Mari
AU  - Du, Yuchen
AU  - Braun, Frank K
AU  - Zhang, Huiyuan
AU  - Huang, L Frank
AU  - Xiao, Sophie
AU  - Teo, Wan-Yee
AU  - Lindsay, Holly
AU  - Zhao, Sibo
AU  - Baxter, Patricia
AU  - Su, Jack M F
AU  - Adesina, Adekunle
AU  - Yang, Jianhua
AU  - Brabetz, Sebastian
AU  - Kool, Marcel
AU  - Pfister, Stefan M
AU  - Chintagumpala, Murali
AU  - Perlaky, Laszlo
AU  - Wang, Zhong
AU  - Zhou, Youxin
AU  - Man, Tsz-Kwong
AU  - Li, Xiao-Nan
TI  - Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion.
JO  - Advanced science
VL  - 8
IS  - 23
SN  - 2198-3844
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2021-02389
SP  - e2101923
PY  - 2021
N1  - 2021 Dec;8(23):e2101923
AB  - Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBMINV ) and tumor core (GBMTC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBMINV and GBMTC cells reveals a significantly elevated invasion capacity in GBMINV cells, detects 23/768 miRNAs over-expressed in the GBMINV cells (miRNAINV ) and 22/768 in the GBMTC cells (miRNATC ), respectively. Silencing the top 3 miRNAsINV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBMINV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNAINV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4-aminopyridine (4-AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBMINV and GBMTC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis.
KW  - 4-aminopyridine (Other)
KW  - KCNA1 (Other)
KW  - glioblastoma (Other)
KW  - miRNA (Other)
KW  - patient derived orthotopic xenograft (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34719887
DO  - DOI:10.1002/advs.202101923
UR  - https://inrepo02.dkfz.de/record/177255
ER  -