Journal Article

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

Snyder, K. M., Sarkar, A., Fajardo, E., Ness, J., Zepecki, J. P., Tapinos, N., Moreno, M. M., Fiser, A., Toms, S. A.

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/95 / 14/1 / 14/19 / 38/77 / 38/91 / 59 / 631/67/1922 / 631/67/71 / 631/80/304 / 96/100 / 96/63 / Animals / Apoptosis / Axonogenesis / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain tumors / Cancer / Cancer genetics / Cell adhesion & migration / Cell Biology / Cell culture / Cell migration / Cell Movement - drug effects / Cell self-renewal / Cells, Cultured / Coculture Techniques / Development and progression / Dorsal root ganglia / Dosage and administration / Drug therapy / Ganglia, Spinal - cytology / Ganglia, Spinal - metabolism / Ganglion cysts / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene regulation / Genes / Genetic aspects / Glioblastoma / Glioblastomas / Glioma / Glioma - drug therapy / Glioma - genetics / Glioma - metabolism / Glioma cells / Gliomas / Human Genetics / Human migration / Humans / Internal Medicine / Kinase inhibitors / Kinases / Lck protein / Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics / Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism / Male / Medicine / Medicine & Public Health / Mice / Molecular modelling / Neoplastic Stem Cells - drug effects / Oligodendroglia - cytology / Oligodendroglia - metabolism / Oncology / Parenchyma / Paxillin / Paxillin - genetics / Paxillin - metabolism / Phosphorylation / Phosphorylation - drug effects / Proto-Oncogene Proteins c-crk - genetics / Proto-Oncogene Proteins c-crk - metabolism / Pseudopodia / Pseudopodia - genetics / Pseudopodia - metabolism / Pyrazoles - administration & dosage / Pyrazoles - pharmacology / Pyrimidines - administration & dosage / Pyrimidines - pharmacology / rac1 GTP-Binding Protein - genetics / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Ribonucleic acid / RNA / Statistical analysis / Stem cells / Therapeutic applications / Tumors / Xenograft Model Antitumor Assays / Xenografts