PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response
Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (16), p.1-12 |
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| creator | Li, Jie Kaneda, Megan M. Ma, Jun Li, Ming Shepard, Ryan M. Patel, Kunal Koga, Tomoyuki Sarver, Aaron Furnari, Frank Xu, Beibei Dhawan, Sanjay Ning, Jianfang Zhu, Hua Wu, Anhua You, Gan Jiang, Tao Venteicher, Andrew S. Rich, Jeremy N. Glass, Christopher K. Varner, Judith A. Chen, Clark C. |
| description | Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy. |
| doi_str_mv | 10.1073/pnas.2009290118 |
| format | Article |
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Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2009290118</identifier><identifier>PMID: 33846242</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Accumulation ; Adult ; Animal models ; Animals ; Biological Sciences ; Brain Neoplasms - pathology ; Cell Line, Tumor ; Chemotherapy ; Class Ib Phosphatidylinositol 3-Kinase - metabolism ; Deactivation ; Drug Resistance, Neoplasm - physiology ; Female ; Glioblastoma ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Glioblastoma cells ; Humans ; Inactivation ; Interleukin 1 ; Interleukin 11 ; Interleukin-11 - immunology ; Interleukin-11 - metabolism ; Kinases ; Macrophages ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Microglia ; Microglia - metabolism ; Microglia - physiology ; Myc protein ; Phosphatidylinositol 3-Kinase - metabolism ; Phosphoinositide-3 Kinase Inhibitors - pharmacology ; Precision medicine ; Signal Transduction - drug effects ; Signaling ; Stat3 protein ; Stem cells ; Temozolomide ; Temozolomide - metabolism ; Temozolomide - pharmacology ; Tumor microenvironment ; Tumor Microenvironment - drug effects ; Tumor-Associated Macrophages - metabolism ; Tumor-Associated Macrophages - physiology ; Tumorigenicity ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-04, Vol.118 (16), p.1-12</ispartof><rights>Copyright National Academy of Sciences Apr 20, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-59163d0459940a8bfd1debc39cd48c7c4d6fe87854c2743006d39ec94dbff8393</citedby><cites>FETCH-LOGICAL-c443t-59163d0459940a8bfd1debc39cd48c7c4d6fe87854c2743006d39ec94dbff8393</cites><orcidid>0000-0001-9544-2570 ; 0000-0001-5199-7742 ; 0000-0002-9251-0600 ; 0000-0003-0427-8205 ; 0000-0003-0643-0493 ; 0000-0002-2540-1738 ; 0000-0003-1909-4361 ; 0000-0002-7488-369X ; 0000-0002-3402-1884 ; 0000-0003-4344-3592 ; 0000-0002-8330-117X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27039892$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27039892$$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/33846242$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Jie</creatorcontrib><creatorcontrib>Kaneda, Megan M.</creatorcontrib><creatorcontrib>Ma, Jun</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Shepard, Ryan M.</creatorcontrib><creatorcontrib>Patel, Kunal</creatorcontrib><creatorcontrib>Koga, Tomoyuki</creatorcontrib><creatorcontrib>Sarver, Aaron</creatorcontrib><creatorcontrib>Furnari, Frank</creatorcontrib><creatorcontrib>Xu, Beibei</creatorcontrib><creatorcontrib>Dhawan, Sanjay</creatorcontrib><creatorcontrib>Ning, Jianfang</creatorcontrib><creatorcontrib>Zhu, Hua</creatorcontrib><creatorcontrib>Wu, Anhua</creatorcontrib><creatorcontrib>You, Gan</creatorcontrib><creatorcontrib>Jiang, Tao</creatorcontrib><creatorcontrib>Venteicher, Andrew S.</creatorcontrib><creatorcontrib>Rich, Jeremy N.</creatorcontrib><creatorcontrib>Glass, Christopher K.</creatorcontrib><creatorcontrib>Varner, Judith A.</creatorcontrib><creatorcontrib>Chen, Clark C.</creatorcontrib><title>PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.</description><subject>Accumulation</subject><subject>Adult</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Class Ib Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Deactivation</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>Female</subject><subject>Glioblastoma</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma cells</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Interleukin 1</subject><subject>Interleukin 11</subject><subject>Interleukin-11 - immunology</subject><subject>Interleukin-11 - metabolism</subject><subject>Kinases</subject><subject>Macrophages</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Microglia</subject><subject>Microglia - metabolism</subject><subject>Microglia - physiology</subject><subject>Myc protein</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors - pharmacology</subject><subject>Precision medicine</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Stat3 protein</subject><subject>Stem cells</subject><subject>Temozolomide</subject><subject>Temozolomide - metabolism</subject><subject>Temozolomide - pharmacology</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Tumor-Associated Macrophages - metabolism</subject><subject>Tumor-Associated Macrophages - 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pathology</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Class Ib Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Deactivation</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>Female</topic><topic>Glioblastoma</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Glioblastoma cells</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Interleukin 1</topic><topic>Interleukin 11</topic><topic>Interleukin-11 - immunology</topic><topic>Interleukin-11 - metabolism</topic><topic>Kinases</topic><topic>Macrophages</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Microglia</topic><topic>Microglia - metabolism</topic><topic>Microglia - physiology</topic><topic>Myc protein</topic><topic>Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors - pharmacology</topic><topic>Precision medicine</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Stat3 protein</topic><topic>Stem cells</topic><topic>Temozolomide</topic><topic>Temozolomide - metabolism</topic><topic>Temozolomide - pharmacology</topic><topic>Tumor microenvironment</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Tumor-Associated Macrophages - metabolism</topic><topic>Tumor-Associated Macrophages - physiology</topic><topic>Tumorigenicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Jie</creatorcontrib><creatorcontrib>Kaneda, Megan M.</creatorcontrib><creatorcontrib>Ma, Jun</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Shepard, Ryan M.</creatorcontrib><creatorcontrib>Patel, Kunal</creatorcontrib><creatorcontrib>Koga, Tomoyuki</creatorcontrib><creatorcontrib>Sarver, Aaron</creatorcontrib><creatorcontrib>Furnari, Frank</creatorcontrib><creatorcontrib>Xu, Beibei</creatorcontrib><creatorcontrib>Dhawan, Sanjay</creatorcontrib><creatorcontrib>Ning, Jianfang</creatorcontrib><creatorcontrib>Zhu, Hua</creatorcontrib><creatorcontrib>Wu, Anhua</creatorcontrib><creatorcontrib>You, Gan</creatorcontrib><creatorcontrib>Jiang, Tao</creatorcontrib><creatorcontrib>Venteicher, Andrew S.</creatorcontrib><creatorcontrib>Rich, Jeremy N.</creatorcontrib><creatorcontrib>Glass, Christopher K.</creatorcontrib><creatorcontrib>Varner, Judith A.</creatorcontrib><creatorcontrib>Chen, Clark C.</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Jie</au><au>Kaneda, Megan M.</au><au>Ma, Jun</au><au>Li, Ming</au><au>Shepard, Ryan M.</au><au>Patel, Kunal</au><au>Koga, Tomoyuki</au><au>Sarver, Aaron</au><au>Furnari, Frank</au><au>Xu, Beibei</au><au>Dhawan, Sanjay</au><au>Ning, Jianfang</au><au>Zhu, Hua</au><au>Wu, Anhua</au><au>You, Gan</au><au>Jiang, Tao</au><au>Venteicher, Andrew S.</au><au>Rich, Jeremy N.</au><au>Glass, Christopher K.</au><au>Varner, Judith A.</au><au>Chen, Clark C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2021-04-20</date><risdate>2021</risdate><volume>118</volume><issue>16</issue><spage>1</spage><epage>12</epage><pages>1-12</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>33846242</pmid><doi>10.1073/pnas.2009290118</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-9544-2570</orcidid><orcidid>https://orcid.org/0000-0001-5199-7742</orcidid><orcidid>https://orcid.org/0000-0002-9251-0600</orcidid><orcidid>https://orcid.org/0000-0003-0427-8205</orcidid><orcidid>https://orcid.org/0000-0003-0643-0493</orcidid><orcidid>https://orcid.org/0000-0002-2540-1738</orcidid><orcidid>https://orcid.org/0000-0003-1909-4361</orcidid><orcidid>https://orcid.org/0000-0002-7488-369X</orcidid><orcidid>https://orcid.org/0000-0002-3402-1884</orcidid><orcidid>https://orcid.org/0000-0003-4344-3592</orcidid><orcidid>https://orcid.org/0000-0002-8330-117X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2021-04, Vol.118 (16), p.1-12 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8072253 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Accumulation Adult Animal models Animals Biological Sciences Brain Neoplasms - pathology Cell Line, Tumor Chemotherapy Class Ib Phosphatidylinositol 3-Kinase - metabolism Deactivation Drug Resistance, Neoplasm - physiology Female Glioblastoma Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma - pathology Glioblastoma cells Humans Inactivation Interleukin 1 Interleukin 11 Interleukin-11 - immunology Interleukin-11 - metabolism Kinases Macrophages Male Mice Mice, Inbred C57BL Mice, Nude Microglia Microglia - metabolism Microglia - physiology Myc protein Phosphatidylinositol 3-Kinase - metabolism Phosphoinositide-3 Kinase Inhibitors - pharmacology Precision medicine Signal Transduction - drug effects Signaling Stat3 protein Stem cells Temozolomide Temozolomide - metabolism Temozolomide - pharmacology Tumor microenvironment Tumor Microenvironment - drug effects Tumor-Associated Macrophages - metabolism Tumor-Associated Macrophages - physiology Tumorigenicity Tumors |
| title | PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T08%3A54%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PI3K%CE%B3%20inhibition%20suppresses%20microglia/TAM%20accumulation%20in%20glioblastoma%20microenvironment%20to%20promote%20exceptional%20temozolomide%20response&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Li,%20Jie&rft.date=2021-04-20&rft.volume=118&rft.issue=16&rft.spage=1&rft.epage=12&rft.pages=1-12&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.2009290118&rft_dat=%3Cjstor_pubme%3E27039892%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2515758583&rft_id=info:pmid/33846242&rft_jstor_id=27039892&rfr_iscdi=true |