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Oncogene. 2019 Mar;38(10):1734-1750. doi: 10.1038/s41388-018-0546-z. Epub 2018 Oct 23.

Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor.

Author information

1
Molecular Neuroscience & Neuro-Oncology Laboratory, Brown University, Providence, RI, USA.
2
University of Minnesota, College of Veterinary Medicine, St. Paul, MN, USA.
3
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
4
Department of Biological Sciences, Messiah College, Mechanicsburg, PA, USA.
5
Department of Neurosurgery, Geisinger Clinic, Danville, PA, USA.
6
Department of Neurosurgery, Brown University, Rhode Island Hospital, Providence, RI, USA.
7
Molecular Neuroscience & Neuro-Oncology Laboratory, Brown University, Providence, RI, USA. nikos_tapinos@brown.edu.
8
Department of Neurosurgery, Brown University, Rhode Island Hospital, Providence, RI, USA. nikos_tapinos@brown.edu.

Abstract

Migration of human glioma cells (hGCs) within the brain parenchyma makes glioblastoma one of the most aggressive and lethal tumors. Studies of the cellular and molecular mechanisms underlying hGC migration are hindered by the limitations of existing glioma models. Here we developed a dorsal root ganglion axon-oligodendrocyte-hGC co-culture to study in real time the migration and interaction of hGCs with their microenvironment. hGCs interact with myelinated and non-myelinated axons through the formation of pseudopodia. Isolation of pseudopodia-localized polysome-bound RNA reveals transcripts of Lck, Paxillin, Crk-II, and Rac1 that undergo local translation. Inhibition of Lck phosphorylation using a small-molecule inhibitor (Lck-I), blocks the phosphorylation of Paxillin and Crk-II, the formation of pseudopodia and the migration of hGCs. In vivo intraventricular administration of the Lck-I using an orthotopic xenograft glioma model, results in statistically significant inhibition of tumor size and significant down-regulation of Nanog-targeted genes, which are associated with glioblastoma patient survival. Moreover, treatment of human glioma stem cells (hGSCs) with Lck-I, results in significant inhibition of self-renewal and tumor-sphere formation. The involvement of Lck in different levels of glioma malignant progression, such as migration, tumor growth, and regulation of cancer stemness, makes Lck a potentially important therapeutic target for human glioblastomas.

PMID:
30353164
PMCID:
PMC6462869
DOI:
10.1038/s41388-018-0546-z
[Indexed for MEDLINE]
Free PMC Article

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