Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3
Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GS...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-05, Vol.110 (21), p.8644-8649 |
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| creator | Mao, Ping Joshi, Kaushal Li, Jianfeng Kim, Sung-Hak Li, Peipei Santana-Santos, Lucas Luthra, Soumya Chandran, Uma R. Benos, Panayiotis V. Smith, Luke Wang, Maode Hu, Bo Cheng, Shi-Yuan Sobol, Robert W. Nakano, Ichiro |
| description | Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. |
| doi_str_mv | 10.1073/pnas.1221478110 |
| format | Article |
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However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1221478110</identifier><identifier>PMID: 23650391</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>aldehyde dehydrogenase ; Aldehyde Dehydrogenase - biosynthesis ; Aldehyde Dehydrogenase - genetics ; Aldehyde Oxidoreductases ; Aldehydes ; Animals ; Biological Sciences ; brain ; Brain neoplasms ; Cancer ; Cell lines ; Cell Proliferation ; Dehydrogenases ; Enzymes ; Female ; Gene Expression Regulation, Enzymologic - genetics ; Gene Expression Regulation, Neoplastic - genetics ; Genes ; Genotype & phenotype ; Glioblastoma ; Glioma ; Glioma - enzymology ; Glioma - pathology ; Glycolysis ; Humans ; Male ; Mesenchymal Stromal Cells - enzymology ; Mesenchymal Stromal Cells - pathology ; messenger RNA ; Metabolism ; Mice ; Neoplasm Proteins - biosynthesis ; Neoplasm Proteins - genetics ; Neoplasm Transplantation ; Neoplastic Stem Cells - enzymology ; Neoplastic Stem Cells - pathology ; phenotype ; Phenotypes ; Rodents ; Signal Transduction ; Stem cells ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-05, Vol.110 (21), p.8644-8649</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences May 21, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-796ae07ec89c3e61ff30931c683db21022944c93978cfc46cdab1a0ef782d65f3</citedby><cites>FETCH-LOGICAL-c590t-796ae07ec89c3e61ff30931c683db21022944c93978cfc46cdab1a0ef782d65f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/21.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42656776$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42656776$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23650391$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mao, Ping</creatorcontrib><creatorcontrib>Joshi, Kaushal</creatorcontrib><creatorcontrib>Li, Jianfeng</creatorcontrib><creatorcontrib>Kim, Sung-Hak</creatorcontrib><creatorcontrib>Li, Peipei</creatorcontrib><creatorcontrib>Santana-Santos, Lucas</creatorcontrib><creatorcontrib>Luthra, Soumya</creatorcontrib><creatorcontrib>Chandran, Uma R.</creatorcontrib><creatorcontrib>Benos, Panayiotis V.</creatorcontrib><creatorcontrib>Smith, Luke</creatorcontrib><creatorcontrib>Wang, Maode</creatorcontrib><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Cheng, Shi-Yuan</creatorcontrib><creatorcontrib>Sobol, Robert W.</creatorcontrib><creatorcontrib>Nakano, Ichiro</creatorcontrib><title>Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.</description><subject>aldehyde dehydrogenase</subject><subject>Aldehyde Dehydrogenase - biosynthesis</subject><subject>Aldehyde Dehydrogenase - genetics</subject><subject>Aldehyde Oxidoreductases</subject><subject>Aldehydes</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>brain</subject><subject>Brain neoplasms</subject><subject>Cancer</subject><subject>Cell lines</subject><subject>Cell Proliferation</subject><subject>Dehydrogenases</subject><subject>Enzymes</subject><subject>Female</subject><subject>Gene Expression Regulation, Enzymologic - genetics</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Genes</subject><subject>Genotype & phenotype</subject><subject>Glioblastoma</subject><subject>Glioma</subject><subject>Glioma - enzymology</subject><subject>Glioma - pathology</subject><subject>Glycolysis</subject><subject>Humans</subject><subject>Male</subject><subject>Mesenchymal Stromal Cells - enzymology</subject><subject>Mesenchymal Stromal Cells - pathology</subject><subject>messenger RNA</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Neoplasm Proteins - biosynthesis</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Transplantation</subject><subject>Neoplastic Stem Cells - enzymology</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>phenotype</subject><subject>Phenotypes</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Stem cells</subject><subject>Transplantation, Heterologous</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1vEzEQhlcIREPhzAmwxIVL2vHH2utLpaqiBamIA_RsOV7vxpF3HWwn0v57vCSkwImDNbL8zKPxvFX1GsMFBkEvt6NOF5gQzESDMTypFhgkXnIm4Wm1ACBi2TDCzqoXKW0AQNYNPK_OCOU1UIkXVf5ikx3Nehq0R713YdAoZTsgY71PSEeLBu3GXI5t0WpC2mS317lcej-Z4KfsDBps1qvgXRqQG_fB793YI-1bu55ai36VGHpbhrUIX9OX1bNO-2RfHet59XD78fvNp-X917vPN9f3S1NLyEshubYgrGmkoZbjrqMgKTa8oe2KYCBEMmYklaIxnWHctHqFNdhONKTldUfPq6uDd7tbDbY1dsxRe7WNbtBxUkE79ffL6NaqD3tFOeeCkiL4cBTE8GNnU1aDS_Nm9GjDLincAC05kPo_UFozISljvKDv_0E3YRfHsomZ4kC4kLhQlwfKxJBStN1pbgxqDl_N4avH8EvH2z-_e-J_p12Ad0dg7jzpio9g1XDGCvHmQGxSDvGEMMJrLgR_NHQ6KN1Hl9TDNwKYA2DaAFD6E3koyY0</recordid><startdate>20130521</startdate><enddate>20130521</enddate><creator>Mao, Ping</creator><creator>Joshi, Kaushal</creator><creator>Li, Jianfeng</creator><creator>Kim, Sung-Hak</creator><creator>Li, Peipei</creator><creator>Santana-Santos, Lucas</creator><creator>Luthra, Soumya</creator><creator>Chandran, Uma R.</creator><creator>Benos, Panayiotis V.</creator><creator>Smith, Luke</creator><creator>Wang, Maode</creator><creator>Hu, Bo</creator><creator>Cheng, Shi-Yuan</creator><creator>Sobol, Robert W.</creator><creator>Nakano, Ichiro</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20130521</creationdate><title>Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3</title><author>Mao, Ping ; Joshi, Kaushal ; Li, Jianfeng ; Kim, Sung-Hak ; Li, Peipei ; Santana-Santos, Lucas ; Luthra, Soumya ; Chandran, Uma R. ; Benos, Panayiotis V. ; Smith, Luke ; Wang, Maode ; Hu, Bo ; Cheng, Shi-Yuan ; Sobol, Robert W. ; Nakano, Ichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c590t-796ae07ec89c3e61ff30931c683db21022944c93978cfc46cdab1a0ef782d65f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>aldehyde dehydrogenase</topic><topic>Aldehyde Dehydrogenase - biosynthesis</topic><topic>Aldehyde Dehydrogenase - genetics</topic><topic>Aldehyde Oxidoreductases</topic><topic>Aldehydes</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>brain</topic><topic>Brain neoplasms</topic><topic>Cancer</topic><topic>Cell lines</topic><topic>Cell Proliferation</topic><topic>Dehydrogenases</topic><topic>Enzymes</topic><topic>Female</topic><topic>Gene Expression Regulation, Enzymologic - genetics</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Genes</topic><topic>Genotype & phenotype</topic><topic>Glioblastoma</topic><topic>Glioma</topic><topic>Glioma - enzymology</topic><topic>Glioma - pathology</topic><topic>Glycolysis</topic><topic>Humans</topic><topic>Male</topic><topic>Mesenchymal Stromal Cells - enzymology</topic><topic>Mesenchymal Stromal Cells - pathology</topic><topic>messenger RNA</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Neoplasm Proteins - biosynthesis</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Transplantation</topic><topic>Neoplastic Stem Cells - enzymology</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>phenotype</topic><topic>Phenotypes</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Stem cells</topic><topic>Transplantation, Heterologous</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Ping</creatorcontrib><creatorcontrib>Joshi, Kaushal</creatorcontrib><creatorcontrib>Li, Jianfeng</creatorcontrib><creatorcontrib>Kim, Sung-Hak</creatorcontrib><creatorcontrib>Li, Peipei</creatorcontrib><creatorcontrib>Santana-Santos, Lucas</creatorcontrib><creatorcontrib>Luthra, Soumya</creatorcontrib><creatorcontrib>Chandran, Uma R.</creatorcontrib><creatorcontrib>Benos, Panayiotis V.</creatorcontrib><creatorcontrib>Smith, Luke</creatorcontrib><creatorcontrib>Wang, Maode</creatorcontrib><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Cheng, Shi-Yuan</creatorcontrib><creatorcontrib>Sobol, Robert W.</creatorcontrib><creatorcontrib>Nakano, Ichiro</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>23650391</pmid><doi>10.1073/pnas.1221478110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2013-05, Vol.110 (21), p.8644-8649 |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | aldehyde dehydrogenase Aldehyde Dehydrogenase - biosynthesis Aldehyde Dehydrogenase - genetics Aldehyde Oxidoreductases Aldehydes Animals Biological Sciences brain Brain neoplasms Cancer Cell lines Cell Proliferation Dehydrogenases Enzymes Female Gene Expression Regulation, Enzymologic - genetics Gene Expression Regulation, Neoplastic - genetics Genes Genotype & phenotype Glioblastoma Glioma Glioma - enzymology Glioma - pathology Glycolysis Humans Male Mesenchymal Stromal Cells - enzymology Mesenchymal Stromal Cells - pathology messenger RNA Metabolism Mice Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics Neoplasm Transplantation Neoplastic Stem Cells - enzymology Neoplastic Stem Cells - pathology phenotype Phenotypes Rodents Signal Transduction Stem cells Transplantation, Heterologous Tumor Cells, Cultured Tumors |
| title | Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3 |
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