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journal article·2021-12Open access

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 Perlaky, Zhong Wang, Youxin Zhou, Tsz‐Kwong Man, Xiao‐Nan Li

Advanced Science· Volume 8· Issue 23
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Abstract

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.
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Research context

OpenAlex topics: MicroRNA in disease regulation · Glioma Diagnosis and Treatment · Extracellular vesicles in disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurosurgery Dushu Lake Hospital Soochow University Suzhou 205124 China

Department of Neurosurgery and Brain and Nerve Research Laboratory the First Affiliated Hospital Soochow University Suzhou 215007 China

Texas Children's Cancer Center Texas Children's Hospital Baylor College of Medicine Houston TX 77030 USA

Program of Precision Medicine PDOX Modeling of Pediatric Tumors Ann & Robert H. Lurie Children's Hospital of Chicago Department of Pediatrics Northwestern University Feinberg School of Medicine Chicago IL 60611 USA

Department of Pharmacology School of Medicine Sun Yat‐Sen University Shenzhen 518107 China

Department of Systems Medicine and Bioegineering Houston Methodist Hospital Research Institute and Cancer Center Weill Cornell Medicine Houston TX 77030 USA

Division of Experimental Hematology and Cancer Biology Brain Tumor Center Cincinnati Children’s Hospital Medical Center Department of Pediatrics University of Cincinnati College of Medicine Cincinnati United States 45229 United States

Humphrey Oei Institute of Cancer Research National Cancer Center Singapore Singapore 169610 Singapore

Department of Pathology Texas Children's Hospital Baylor College of Medicine Houston TX 77030 USA

Hopp Children's Cancer Center (KiTZ) Heidelberg 69120 Germany

Division of Pediatric Neuro‐oncology German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) Heidelberg 69120 Germany

Department of Pediatric Hematology and Oncology Heidelberg University Hospital Heidelberg 69120 Germany

Funding

National Natural Science Foundation of China · St. Baldrick's Foundation · Cancer Prevention and Research Institute of Texas · National Institutes of Health

References (63)

Show source-provided references
1. 10.1038/s41591-018-0086-710.1038/s41591-018-0086-7 ↗
2. 10.1007/s00401-017-1710-110.1007/s00401-017-1710-1 ↗
3. 10.1126/science.aaf266610.1126/science.aaf2666 ↗
4. 10.1200/JCO.2017.73.024210.1200/JCO.2017.73.0242 ↗
5. 10.1038/s41571-019-0177-510.1038/s41571-019-0177-5 ↗
6. 10.1093/neuonc/nox14810.1093/neuonc/nox148 ↗
7. 10.1056/NEJMoa04333010.1056/NEJMoa043330 ↗
8. 10.1038/nrn376510.1038/nrn3765 ↗
9. 10.1186/s12964-017-0194-x10.1186/s12964-017-0194-x ↗
10. 10.1007/s00401-011-0940-x10.1007/s00401-011-0940-x ↗
11. 10.1016/j.yexcr.2017.08.03210.1016/j.yexcr.2017.08.032 ↗
12. 10.1038/s41580-018-0080-410.1038/s41580-018-0080-4 ↗
13. 10.1002/cncr.2362410.1002/cncr.23624 ↗
14. 10.1158/1078-0432.CCR-17-225610.1158/1078-0432.CCR-17-2256 ↗
15. 10.1634/stemcells.2007-100910.1634/stemcells.2007-1009 ↗
16. 10.1093/neuonc/nos06110.1093/neuonc/nos061 ↗
17. 10.1038/nature0287110.1038/nature02871 ↗
18. 10.1016/j.cell.2009.01.00210.1016/j.cell.2009.01.002 ↗
19. 10.3892/ijo.2015.284110.3892/ijo.2015.2841 ↗
20. 10.1016/j.neuron.2009.10.02010.1016/j.neuron.2009.10.020 ↗
21. 10.1073/pnas.070762810410.1073/pnas.0707628104 ↗
22. 10.1038/srep0084210.1038/srep00842 ↗
23. 10.4161/cc.2645910.4161/cc.26459 ↗
24. 10.1007/s12015-017-9788-310.1007/s12015-017-9788-3 ↗
25. 10.1128/MCB.00479-0810.1128/MCB.00479-08 ↗
26. Spijker S. · 2011
27. 10.1038/nature2600010.1038/nature26000 ↗
28. 10.1038/nrc365510.1038/nrc3655 ↗
29. 10.18632/oncotarget.2071310.18632/oncotarget.20713 ↗
30. 10.1093/neuonc/nop05610.1093/neuonc/nop056 ↗
31. 10.3390/ijms1811245210.3390/ijms18112452 ↗
32. 10.1371/journal.pone.024432510.1371/journal.pone.0244325 ↗
33. 10.1055/s-0039-168517010.1055/s-0039-1685170 ↗
34. 10.1007/s00381-017-3381-610.1007/s00381-017-3381-6 ↗
35. 10.1093/neuonc/nou33710.1093/neuonc/nou337 ↗
36. 10.1002/stem.1510.1002/stem.15 ↗
37. 10.1038/nature0370210.1038/nature03702 ↗
38. 10.1007/s12035-012-8349-710.1007/s12035-012-8349-7 ↗
39. 10.1038/nature0617410.1038/nature06174 ↗
40. 10.1007/s00109-007-0296-910.1007/s00109-007-0296-9 ↗
41. 10.1038/onc.2013.33510.1038/onc.2013.335 ↗
42. 10.1038/cdd.2014.11210.1038/cdd.2014.112 ↗
43. 10.1093/nar/gku100310.1093/nar/gku1003 ↗
44. 10.1074/jbc.M20699520010.1074/jbc.M206995200 ↗
45. 10.1111/j.1600-0854.2010.01051.x10.1111/j.1600-0854.2010.01051.x ↗
46. 10.1101/gr.259650410.1101/gr.2596504 ↗
47. Shibuya M. · Oncogene · 1990 · 5 · 519
48. 10.1002/art.2101310.1002/art.21013 ↗
49. 10.1172/JCI3694810.1172/JCI36948 ↗
50. 10.1038/nrd298310.1038/nrd2983 ↗
51. 10.1038/nrd.2015.2110.1038/nrd.2015.21 ↗
52. 10.1517/1354378090300208210.1517/13543780903002082 ↗
53. 10.1016/j.clinthera.2009.02.00410.1016/j.clinthera.2009.02.004 ↗
54. 10.1177/175628561351271210.1177/1756285613512712 ↗
55. 10.1016/0920-1211(92)90016-M10.1016/0920-1211(92)90016-M ↗
56. 10.1016/j.molcel.2008.05.00110.1016/j.molcel.2008.05.001 ↗
57. 10.1016/j.cell.2018.07.04010.1016/j.cell.2018.07.040 ↗
58. 10.1200/JCO.2009.27.432410.1200/JCO.2009.27.4324 ↗
59. 10.1158/0008-5472.CAN-12-369010.1158/0008-5472.CAN-12-3690 ↗
60. 10.2174/09298671279899209310.2174/092986712798992093 ↗
61. 10.1212/NXI.000000000000097610.1212/NXI.0000000000000976 ↗
62. 10.1093/neuonc/nop05610.1093/neuonc/nop056 ↗
63. 10.1186/gb-2004-5-10-r8010.1186/gb-2004-5-10-r80 ↗