title: c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype.
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 stem cells has not been previously identified. Here, we show that c-Met is activated and functional in glioblastoma (GBM) neurospheres enriched for glioblastoma tumor-initiating 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 glioblastoma cells 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 stem cells (GBM SCs) via a mechanism requiring Nanog and potentially other c-Met-responsive reprogramming transcription factors.
authors.affiliation: Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA. LiYu@kennedykrieger.org
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Li
authors.forename: Angela
authors.initials: A
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Glas
authors.forename: Bachchu
authors.initials: B
authors.lastname: Lal
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.forename: Yingying
authors.initials: Y
authors.lastname: Sang
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.forename: Daniel
authors.initials: D
authors.lastname: Trageser
authors.forename: Hugo
authors.initials: H
authors.lastname: Guerrero-Cázares
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quiñones-Hinojosa
authors.forename: Bjorn
authors.initials: B
authors.lastname: Scheffler
authors.forename: John
authors.initials: J
authors.lastname: Laterra
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D065150:Cellular Reprogramming; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D018398:Homeodomain Proteins; D007211:Indoles; C489427:MYC protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D010455:Peptides; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D013449:Sulfonamides; D019859:Proto-Oncogene Proteins c-met