PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1. (11th November 2019) - Huang, Yulun
Abstract: Diffuse invasion is one of the key features that make GBM particularly difficult to treat. We hypothesize that direct comparison of matched invasive (GBM INV ) and tumor core GBM cells (GBM TC ) would facilitate the discovery of drivers of pediatric GBM (pGBM) invasion. However, GBM INV cells are extremely difficult to obtain from normal brain tissues because aggressive surgical resection of normal tissue carries the risk of serious neurological deficits. Most past and current studies on GBM invasion were and are forced to utilize the resected primary tumor masses. To overcome this barrier, we utilized a panel of 6 pediatric patient tumor-derived orthotopic xenograft (PDOX) mouse models to isolate matching pairs of GBM TC cells and GBM INV cells and confirmed a significantly elevated invasive capacity in GBM INV cells both in vitro and in vivo . Global profiling of 768 human microRNA using a real-time PCR-based Taqman system identified 23 microRNAs were upregulated in the GBM INV cells in at least 4 of the 6 pGBM models as compared with the matching GBM TC cells. We subsequently showed that silencing the top three miRNA INV, miR-126, miR-369-5p, and miR-487b, suppressed tumor cell migration in vitro (both as neurospheres and monolayer cultures) without affecting cell proliferation, and blocked pGBM invasion in mouse brains. Integrated analysis of the mRNA profiling of the same set of GBM TC and GBM INV cells revealed the affected signaling pathways and identified KCNA1 as the sole common computational target gene of the three miRNA INV . Treatment of three pairs of GBM TC and GBM INV cells with two KCNA1 inhibitors, ADWX1 and Agitoxin 2, caused significant suppression of pGBM cell migration in vitro . In conclusion, this study revealed an intrinsically elevated invasive phenotype in GBM INV cells, identified miR-126, -369-5p, and -487b as novel drivers of pGBM invasion, and characterized KCNA1 as a potential therapeutic target for arresting pGBM invasion.