TY - JOUR
T1 - Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor
AU - Zepecki, J. P.
AU - Snyder, K. M.
AU - Moreno, M. M.
AU - Fajardo, E.
AU - Fiser, A.
AU - Ness, J.
AU - Sarkar, A.
AU - Toms, S. A.
AU - Tapinos, N.
N1 - Funding Information:
Acknowledgements We thank members of the Tapinos lab for critically reviewing the manuscript. We would like to thank Kara Lom-bardo and Ashlee Sturtevant at the Pathology Core of Rhode Island Hospital for the assistance with glioblastoma tissue sections and stainings. We also thank Oliver Tang for analysis of the TCGA dataset. All animal work was performed according to institutional guidelines and approved by the IACUC committee of Rhode Island Hospital and Geisinger Clinic. Work included in this publication was supported by the Molecular Pathology Core of the COBRE Center for Cancer Research Development, funded by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P30GM110759. This research project was also supported by institutional funds of the Geisinger Clinic to N.T., S.A.T., and A.S. and by institutional funds of the Department of Neurosurgery of Brown University to N.T. and S.A.T.
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/3/7
Y1 - 2019/3/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-018-0546-z
DO - 10.1038/s41388-018-0546-z
M3 - Article
C2 - 30353164
AN - SCOPUS:85055500714
SN - 0950-9232
VL - 38
SP - 1734
EP - 1750
JO - Oncogene
JF - Oncogene
IS - 10
ER -
