c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype

Yunqing Li, Angela Li, Martin Glas, Bachchu Lal, Mingyao Ying, Yingying Sang, Shuli Xia, Daniel Trageser, Hugo Guerrero-Cázares, Charles G. Eberhart, Alfredo Quiñones-Hinojosa, Bjorn Scheffler, John Laterra

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

The tyrosine kinase c-Met promotes the formation and malignant progression of multiple cancers. It is well known that c-Met hyperactivation increases tumorigenicity and tumor cell resistance to DNA damaging agents, properties associated with tumor-initiating stem cells. However, a link between c-Met signaling and the formation and/or maintenance of neoplastic stemcells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumorinitiating stem cells and that c-Met expression/function correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres and clinical glioblastoma specimens. c-Met activation was found to induce the expression of reprogramming transcription factors (RFs) known to support embryonic stem cells and induce differentiated cells to form pluripotent stem(iPS) cells, and c-Met activation counteracted the effects of forced differentiation in glioblastoma neurospheres. Expression of the reprogramming transcription factor Nanog by glioblastomacells is shown to mediate the ability of c-Met to induce the stem cell characteristics of neurosphere formation and neurosphere cell self-renewal. These findings show that c-Met enhances the population of glioblastoma stemcells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met - responsive reprogramming transcription factors.

Original languageEnglish (US)
Pages (from-to)9951-9956
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number24
DOIs
StatePublished - Jun 14 2011

Keywords

  • Cancer stem cell
  • Hepatocyte growth factor
  • Klf4
  • Oct4
  • Sox2

ASJC Scopus subject areas

  • General

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