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Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655179/ https://www.ncbi.nlm.nih.gov/pubmed/34719887 http://dx.doi.org/10.1002/advs.202101923 |
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author | Huang, Yulun Qi, Lin Kogiso, Mari Du, Yuchen Braun, Frank K. Zhang, Huiyuan Huang, L. Frank Xiao, Sophie Teo, Wan‐Yee Lindsay, Holly Zhao, Sibo Baxter, Patricia Su, Jack M. F. Adesina, Adekunle Yang, Jianhua Brabetz, Sebastian Kool, Marcel Pfister, Stefan M. Chintagumpala, Murali Perlaky, Laszlo Wang, Zhong Zhou, Youxin Man, Tsz‐Kwong Li, Xiao‐Nan |
author_facet | Huang, Yulun Qi, Lin Kogiso, Mari Du, Yuchen Braun, Frank K. Zhang, Huiyuan Huang, L. Frank Xiao, Sophie Teo, Wan‐Yee Lindsay, Holly Zhao, Sibo Baxter, Patricia Su, Jack M. F. Adesina, Adekunle Yang, Jianhua Brabetz, Sebastian Kool, Marcel Pfister, Stefan M. Chintagumpala, Murali Perlaky, Laszlo Wang, Zhong Zhou, Youxin Man, Tsz‐Kwong Li, Xiao‐Nan |
author_sort | Huang, Yulun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8655179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86551792021-12-20 Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion Huang, Yulun Qi, Lin Kogiso, Mari Du, Yuchen Braun, Frank K. Zhang, Huiyuan Huang, L. Frank Xiao, Sophie Teo, Wan‐Yee Lindsay, Holly Zhao, Sibo Baxter, Patricia Su, Jack M. F. Adesina, Adekunle Yang, Jianhua Brabetz, Sebastian Kool, Marcel Pfister, Stefan M. Chintagumpala, Murali Perlaky, Laszlo Wang, Zhong Zhou, Youxin Man, Tsz‐Kwong Li, Xiao‐Nan Adv Sci (Weinh) Research Articles 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. John Wiley and Sons Inc. 2021-11-01 /pmc/articles/PMC8655179/ /pubmed/34719887 http://dx.doi.org/10.1002/advs.202101923 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Huang, Yulun Qi, Lin Kogiso, Mari Du, Yuchen Braun, Frank K. Zhang, Huiyuan Huang, L. Frank Xiao, Sophie Teo, Wan‐Yee Lindsay, Holly Zhao, Sibo Baxter, Patricia Su, Jack M. F. Adesina, Adekunle Yang, Jianhua Brabetz, Sebastian Kool, Marcel Pfister, Stefan M. Chintagumpala, Murali Perlaky, Laszlo Wang, Zhong Zhou, Youxin Man, Tsz‐Kwong Li, Xiao‐Nan Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title | Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title_full | Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title_fullStr | Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title_full_unstemmed | Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title_short | Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion |
title_sort | spatial dissection of invasive front from tumor mass enables discovery of novel microrna drivers of glioblastoma invasion |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655179/ https://www.ncbi.nlm.nih.gov/pubmed/34719887 http://dx.doi.org/10.1002/advs.202101923 |
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