Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion.

ABSTRACT: 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 (GBM^INV ) and tumor core (GBM^TC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBM^INV and GBM^TC cells reveals a significantly elevated invasion capacity in GBM^INV cells, detects 23/768 miRNAs over-expressed in the GBM^INV cells (miRNA^INV ) and 22/768 in the GBM^TC cells (miRNA^TC ), respectively. Silencing the top 3 miRNAs^INV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBM^INV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNA^INV 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 GBM^INV and GBM^TC 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.

SUBMITTER: Huang Y 

PROVIDER: S-EPMC8655179 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature