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The MET oncogene is a functional marker of a glioblastoma stem cell subtype and drives the invasive phenotype

ABSTRACT: Eighteen independent neurospheres derived from patients affected by primary glioblastoma were grouped into “classical”, “mesenchymal” or “proneural” subtypes according to analysis of genetic lesions and gene expression profiling. Here we show that expression of the MET oncogene, encoding the tyrosine kinase receptor for HGF, associates with mesenchymal and proneural neurospheres (Met-pos-NS). Met expression is almost absent from classical neurospheres (Met-neg-NS), and mutually exclusive with amplification and expression of the EGF receptor gene. Met-pos-NS and Met-neg-NS display distinct growth factor requirements, differentiate along divergent pathways, and generate tumors with distinctive histological features. Met-pos-NS contain a variable percentage of Met positive (Methigh) and Met negative (Metneg) cells. After purification, only Methigh cells display clonogenic ability in vitro, and regenerate neurospheres containing both Methigh and Metneg cells. After in vivo transplantation, Methigh cells display highly enriched tumorigenic potential as compared with Metneg cells. At functional level, in Methigh cells, HGF concomitantly sustains proliferation, clonogenicity, expression of self-renewal markers, migration and invasion. These data show that Met is a functional marker of glioblastoma stem cells, and a candidate target for molecular diagnosis and therapy of a glioblastoma subset.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36426 | GEO | 2012/10/05

SECONDARY ACCESSION(S): PRJNA153229

REPOSITORIES: GEO

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The MET oncogene is a functional marker of a glioblastoma stem cell subtype and drives the invasive phenotype

Project description:Eighteen independent neurospheres derived from patients affected by primary glioblastoma were grouped into “classical”, “mesenchymal” or “proneural” subtypes according to analysis of genetic lesions and gene expression profiling. Here we show that expression of the MET oncogene, encoding the tyrosine kinase receptor for HGF, associates with mesenchymal and proneural neurospheres (Met-pos-NS). Met expression is almost absent from classical neurospheres (Met-neg-NS), and mutually exclusive with amplification and expression of the EGF receptor gene. Met-pos-NS and Met-neg-NS display distinct growth factor requirements, differentiate along divergent pathways, and generate tumors with distinctive histological features. Met-pos-NS contain a variable percentage of Met positive (Methigh) and Met negative (Metneg) cells. After purification, only Methigh cells display clonogenic ability in vitro, and regenerate neurospheres containing both Methigh and Metneg cells. After in vivo transplantation, Methigh cells display highly enriched tumorigenic potential as compared with Metneg cells. At functional level, in Methigh cells, HGF concomitantly sustains proliferation, clonogenicity, expression of self-renewal markers, migration and invasion. These data show that Met is a functional marker of glioblastoma stem cells, and a candidate target for molecular diagnosis and therapy of a glioblastoma subset. 37 samples (17 replicate samples and 1 triplicate sample)

2012-10-05 | E-GEOD-36426 | biostudies-arrayexpress

Liver colonisation by colorectal cancer metastases requires YAP-controlled plasticity at the micrometastatic stage

Project description:Human engineered CRC organoids were equipped with the intestinal stem cell reporter STAR reflecting transcriptional activity of ASCL2. Successfully growing organoids display heterogeneous STAR expression and grow into big structures, while growth-compromised organoids stay small and are either entirely STAR-pos or STAR-neg.

2022-02-23 | GSE193248 | GEO

Effect of loss of Gfi1b on hematopietic stem cells

Project description:Using Gfi1b conditional mice, deletion of gfi1b in the hematopietic system was induced by injecting MxCre tg Gfi1bfl/fl mice with pIpC. 30 days after injection, Cd150 pos, Cd 48 neg, Lin neg Sca and c-kit pos stem cells were sortrted from Gfi1bfl/fl and Mxcre tg Gfi1bfl/fl mice and analysed. We used the mouse Affymetrix Gene ST Array.

2010-09-03 | GSE20655 | GEO

Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation

Project description:Mammals differ more than 100-fold in maximum lifespan. Here, we conducted comparative transcriptomics on 26 species with diverse lifespans. We identified thousands of genes with expression levels negatively or positively correlated with a species' maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is modulated by interventions, including mTOR and PI3K inhibition. Regulatory networks analysis showed that Neg-MLS genes are under circadian regulation possibly to avoid persistent high expression, whereas Pos-MLS genes are targets of master pluripotency regulators OCT4 and NANOG and are upregulated during somatic cell reprogramming. Pos-MLS genes are highly expressed during embryogenesis but significantly downregulated after birth. This work provides targets for anti-aging interventions by defining pathways correlating with longevity across mammals and uncovering circadian and pluripotency networks as central regulators of longevity.

2022-05-18 | GSE190756 | GEO

Effect of loss of Gfi1b on hematopietic stem cells

2010-09-03 | E-GEOD-20655 | biostudies-arrayexpress

Prtg+ve Rhombic Lip Ventricular Zone Stem Cells Initiate and Maintain Group 3 Medulloblastoma [prtg_sort_scRNAseq]

Project description:We sorted Group 3 MB xenografts tumors by PRTG surface expression and performed single-cell RNA sequencing on the PRTG-pos and PRTG-neg fractions.

2024-08-06 | GSE206897 | GEO

Angiogenesis and Gene Signature in Muscular Hypertrophy

Project description:Adult myogenic progenitor cells (activated satellite cells) express both HGF and its receptor cMet. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells. Magic-F1 (Met-Activating Genetically Improved Chimeric Factor-1) is an HGF-derived, engineered protein that contains two Met-binding domains that promotes muscle hypertrophy, protecting myogenic precursors against apoptosis, increasing their fusion ability and enhancing muscle differentiation. Hemizygous and homozygous Magic-F1 transgenic mice displayed constitutive muscle hypertrophy. We described here microarray analysis on Magic-F1 myogenic progenitor cells showing an altered gene signatures involving muscle hypertrophy and vasculogenesis compared to wild-type cells. In parallel, we performed a functional analysis on homozygous Magic-F1 transgenic mice versus control, demonstrating that Magic-F1+/+ mice display impairment on running performance. Finally, we show that induced muscle hypertrophy affects positively vascular network, increasing vessel number in fast twitch fibers. This is due to unique features of mammalian skeletal muscle and its remarkable ability to adapt promptly to different physiological demands by changing gene expression profile. Biological triplicates of Magic-F1+/+ and control satellite cells were used for microarray analysis.

2016-06-28 | E-GEOD-83771 | biostudies-arrayexpress

The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma

Project description:Head and neck squamous cell carcinomas (HNSCC) are known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, there is a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC might influence glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we used three established HNSCC cell lines and flow cytometry, western blot and RNA sequencing. Dynamic changes in glucose metabolism were measured real-time by an Extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by RNA sequencing, the level of Met expression is associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Methigh expressing HNSCC cells. Collectively our data supports the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.

2020-01-17 | GSE135552 | GEO

c-MET inhibitor inducing KSHV+ primary effusion lymphoma apoptosis

Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel âdruggableâ candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo. PEL cells were treated with vehicle control or c-MET inhibitor PF-2341066 (0.8 ÂµM) for 24 h, and the gene expression signature was compared to respective vehicle controls

2016-01-05 | E-GEOD-70594 | biostudies-arrayexpress

c-MET inhibitor inducing KSHV+ primary effusion lymphoma apoptosis

Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel “druggable” candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo.

2016-01-05 | GSE70594 | GEO

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