Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing
The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2 also causes human immunodeficiency, although the mechanism remains unexplai...
Gespeichert in:
| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (52), p.e2310221120-e2310221120 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e2310221120 |
|---|---|
| container_issue | 52 |
| container_start_page | e2310221120 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 120 |
| creator | Mishra, Abhinava K Rodriguez, Melanie Torres, Alba Yurani Smith, Morgan Rodriguez, Anthony Bond, Annalise Morrissey, Meghan A Montell, Denise J |
| description | The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2
also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2
stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2
bone-marrow-derived macrophages also cannibalize primary Rac2
T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2
macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2
also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2
human immunodeficiency and enhance CAR-M cancer immunotherapy. |
| doi_str_mv | 10.1073/pnas.2310221120 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2903859720</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2909193955</sourcerecordid><originalsourceid>FETCH-LOGICAL-c366t-58c9449143787670c359fc64573ed9ba22f8e33e5c249dc313f44337125455483</originalsourceid><addsrcrecordid>eNpdkUtLxDAUhYMoOj7W7iTgxk2dJDdpk6UMvmBEGHRdMmmqGdt0TNoB_72p4wNc3c33HS7nIHRKySUlBUzXXsdLBpQwRikjO2hCiaJZzhXZRRNCWJFJzvgBOoxxRQhRQpJ9dAAyYULQCWrvPtY2aNO7jcULbXDsXTs0urcRG-29W-rGxRZ3NW7cxvkX3OvwYntsbNNErH2FrX_V3iR-drXIHrLWVi7p1agbG75A_OaaJsnHaK_WTbQn3_cIPd9cP83usvnj7f3sap4ZyPM-E9IozhXlUMgiL4gBoWqTc1GArdRSM1ZLC2CFYVxVBijUnAMUlAkuBJdwhC62uevQvQ829mXr4viI9rYbYskUASlUwUhCz_-hq24IPn03UooqSEUlarqlTOhiDLYu18G1OnyUlJTjEuW4RPm3RDLOvnOHZarkl_-pHj4BS-2CsQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2909193955</pqid></control><display><type>article</type><title>Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing</title><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Mishra, Abhinava K ; Rodriguez, Melanie ; Torres, Alba Yurani ; Smith, Morgan ; Rodriguez, Anthony ; Bond, Annalise ; Morrissey, Meghan A ; Montell, Denise J</creator><creatorcontrib>Mishra, Abhinava K ; Rodriguez, Melanie ; Torres, Alba Yurani ; Smith, Morgan ; Rodriguez, Anthony ; Bond, Annalise ; Morrissey, Meghan A ; Montell, Denise J</creatorcontrib><description>The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2
also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2
stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2
bone-marrow-derived macrophages also cannibalize primary Rac2
T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2
macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2
also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2
human immunodeficiency and enhance CAR-M cancer immunotherapy.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2310221120</identifier><identifier>PMID: 38109551</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Bone marrow ; Cancer ; Cancer immunotherapy ; Cannibalism ; Cell Death ; Cell size ; Chimeric antigen receptors ; Hematopoietic stem cells ; Humans ; Hypersensitivity ; Immunodeficiency ; Immunologic Deficiency Syndromes - genetics ; Immunotherapy ; Leukemia ; Lymphocytes ; Lymphocytes T ; Macrophages ; Macrophages - metabolism ; Mice ; Neoplasms ; rac GTP-Binding Proteins - genetics ; rac GTP-Binding Proteins - metabolism ; rac1 GTP-Binding Protein - metabolism ; Rac2 protein ; Receptors, Chimeric Antigen</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-12, Vol.120 (52), p.e2310221120-e2310221120</ispartof><rights>Copyright National Academy of Sciences Dec 26, 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-58c9449143787670c359fc64573ed9ba22f8e33e5c249dc313f44337125455483</citedby><cites>FETCH-LOGICAL-c366t-58c9449143787670c359fc64573ed9ba22f8e33e5c249dc313f44337125455483</cites><orcidid>0000-0001-8924-5925 ; 0009-0005-8720-5686</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38109551$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mishra, Abhinava K</creatorcontrib><creatorcontrib>Rodriguez, Melanie</creatorcontrib><creatorcontrib>Torres, Alba Yurani</creatorcontrib><creatorcontrib>Smith, Morgan</creatorcontrib><creatorcontrib>Rodriguez, Anthony</creatorcontrib><creatorcontrib>Bond, Annalise</creatorcontrib><creatorcontrib>Morrissey, Meghan A</creatorcontrib><creatorcontrib>Montell, Denise J</creatorcontrib><title>Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2
also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2
stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2
bone-marrow-derived macrophages also cannibalize primary Rac2
T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2
macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2
also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2
human immunodeficiency and enhance CAR-M cancer immunotherapy.</description><subject>Animals</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>Cancer immunotherapy</subject><subject>Cannibalism</subject><subject>Cell Death</subject><subject>Cell size</subject><subject>Chimeric antigen receptors</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Hypersensitivity</subject><subject>Immunodeficiency</subject><subject>Immunologic Deficiency Syndromes - genetics</subject><subject>Immunotherapy</subject><subject>Leukemia</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Neoplasms</subject><subject>rac GTP-Binding Proteins - genetics</subject><subject>rac GTP-Binding Proteins - metabolism</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Rac2 protein</subject><subject>Receptors, Chimeric Antigen</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtLxDAUhYMoOj7W7iTgxk2dJDdpk6UMvmBEGHRdMmmqGdt0TNoB_72p4wNc3c33HS7nIHRKySUlBUzXXsdLBpQwRikjO2hCiaJZzhXZRRNCWJFJzvgBOoxxRQhRQpJ9dAAyYULQCWrvPtY2aNO7jcULbXDsXTs0urcRG-29W-rGxRZ3NW7cxvkX3OvwYntsbNNErH2FrX_V3iR-drXIHrLWVi7p1agbG75A_OaaJsnHaK_WTbQn3_cIPd9cP83usvnj7f3sap4ZyPM-E9IozhXlUMgiL4gBoWqTc1GArdRSM1ZLC2CFYVxVBijUnAMUlAkuBJdwhC62uevQvQ829mXr4viI9rYbYskUASlUwUhCz_-hq24IPn03UooqSEUlarqlTOhiDLYu18G1OnyUlJTjEuW4RPm3RDLOvnOHZarkl_-pHj4BS-2CsQ</recordid><startdate>20231226</startdate><enddate>20231226</enddate><creator>Mishra, Abhinava K</creator><creator>Rodriguez, Melanie</creator><creator>Torres, Alba Yurani</creator><creator>Smith, Morgan</creator><creator>Rodriguez, Anthony</creator><creator>Bond, Annalise</creator><creator>Morrissey, Meghan A</creator><creator>Montell, Denise J</creator><general>National Academy of Sciences</general><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><orcidid>https://orcid.org/0000-0001-8924-5925</orcidid><orcidid>https://orcid.org/0009-0005-8720-5686</orcidid></search><sort><creationdate>20231226</creationdate><title>Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing</title><author>Mishra, Abhinava K ; Rodriguez, Melanie ; Torres, Alba Yurani ; Smith, Morgan ; Rodriguez, Anthony ; Bond, Annalise ; Morrissey, Meghan A ; Montell, Denise J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-58c9449143787670c359fc64573ed9ba22f8e33e5c249dc313f44337125455483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Bone marrow</topic><topic>Cancer</topic><topic>Cancer immunotherapy</topic><topic>Cannibalism</topic><topic>Cell Death</topic><topic>Cell size</topic><topic>Chimeric antigen receptors</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Hypersensitivity</topic><topic>Immunodeficiency</topic><topic>Immunologic Deficiency Syndromes - genetics</topic><topic>Immunotherapy</topic><topic>Leukemia</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>Neoplasms</topic><topic>rac GTP-Binding Proteins - genetics</topic><topic>rac GTP-Binding Proteins - metabolism</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Rac2 protein</topic><topic>Receptors, Chimeric Antigen</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mishra, Abhinava K</creatorcontrib><creatorcontrib>Rodriguez, Melanie</creatorcontrib><creatorcontrib>Torres, Alba Yurani</creatorcontrib><creatorcontrib>Smith, Morgan</creatorcontrib><creatorcontrib>Rodriguez, Anthony</creatorcontrib><creatorcontrib>Bond, Annalise</creatorcontrib><creatorcontrib>Morrissey, Meghan A</creatorcontrib><creatorcontrib>Montell, Denise J</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>MEDLINE - Academic</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mishra, Abhinava K</au><au>Rodriguez, Melanie</au><au>Torres, Alba Yurani</au><au>Smith, Morgan</au><au>Rodriguez, Anthony</au><au>Bond, Annalise</au><au>Morrissey, Meghan A</au><au>Montell, Denise J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2023-12-26</date><risdate>2023</risdate><volume>120</volume><issue>52</issue><spage>e2310221120</spage><epage>e2310221120</epage><pages>e2310221120-e2310221120</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2
also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2
stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2
bone-marrow-derived macrophages also cannibalize primary Rac2
T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2
macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2
also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2
human immunodeficiency and enhance CAR-M cancer immunotherapy.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>38109551</pmid><doi>10.1073/pnas.2310221120</doi><orcidid>https://orcid.org/0000-0001-8924-5925</orcidid><orcidid>https://orcid.org/0009-0005-8720-5686</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2023-12, Vol.120 (52), p.e2310221120-e2310221120 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2903859720 |
| source | MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Bone marrow Cancer Cancer immunotherapy Cannibalism Cell Death Cell size Chimeric antigen receptors Hematopoietic stem cells Humans Hypersensitivity Immunodeficiency Immunologic Deficiency Syndromes - genetics Immunotherapy Leukemia Lymphocytes Lymphocytes T Macrophages Macrophages - metabolism Mice Neoplasms rac GTP-Binding Proteins - genetics rac GTP-Binding Proteins - metabolism rac1 GTP-Binding Protein - metabolism Rac2 protein Receptors, Chimeric Antigen |
| title | Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T18%3A58%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hyperactive%20Rac%20stimulates%20cannibalism%20of%20living%20target%20cells%20and%20enhances%20CAR-M-mediated%20cancer%20cell%20killing&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Mishra,%20Abhinava%20K&rft.date=2023-12-26&rft.volume=120&rft.issue=52&rft.spage=e2310221120&rft.epage=e2310221120&rft.pages=e2310221120-e2310221120&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.2310221120&rft_dat=%3Cproquest_cross%3E2909193955%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2909193955&rft_id=info:pmid/38109551&rfr_iscdi=true |