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

Yulun Huang, Lin Qi, Mari Kogiso, Yuchen Du, Frank K. Braun, Huiyuan Zhang, L. Frank Huang, Sophie Xiao, Wan Yee Teo, Holly Lindsay, Sibo Zhao, Patricia Baxter, Jack M.F. Su, Adekunle Adesina, Jianhua Yang, Sebastian Brabetz, Marcel Kool, Stefan M. Pfister, Murali Chintagumpala, Laszlo PerlakyZhong Wang, Youxin Zhou, Tsz Kwong Man, Xiao Nan Li

Research output: Contribution to journalArticlepeer-review

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 (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.

Original languageEnglish (US)
Article number2101923
JournalAdvanced Science
Volume8
Issue number23
DOIs
StatePublished - Dec 8 2021

Keywords

  • 4-aminopyridine
  • KCNA1
  • glioblastoma
  • miRNA
  • patient derived orthotopic xenograft

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering(all)
  • Physics and Astronomy(all)

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