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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Glioma
Cell Movement
Gene Expression
Growth
Pseudopodia
Neoplasms
Glioblastoma
Paxillin
Axons
Phosphorylation
Polyribosomes
Oligodendroglia
Spinal Ganglia
Coculture Techniques
Heterografts
Stem Cells
Down-Regulation
RNA
Survival
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor. / Zepecki, J. P.; Snyder, K. M.; Moreno, M. M.; Fajardo, Jorge E.; Fiser, Andras; Ness, J.; Sarkar, A.; Toms, S. A.; Tapinos, N.

In: Oncogene, 01.01.2018.

Research output: Contribution to journalArticle

Zepecki, J. P. ; Snyder, K. M. ; Moreno, M. M. ; Fajardo, Jorge E. ; Fiser, Andras ; Ness, J. ; Sarkar, A. ; Toms, S. A. ; Tapinos, N. / Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor. In: Oncogene. 2018.
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