Tumor-induced disruption of the blood-brain barrier promotes host death
Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that...
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creator | Kim, Jung Chuang, Hsiu-Chun Wolf, Natalie K. Nicolai, Christopher J. Raulet, David H. Saijo, Kaoru Bilder, David |
description | Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities.
[Display omitted]
•Fly tumors induce paraneoplastic opening of the BBB•BBB permeabilization by tumor-induced JAK/STAT activation accelerates host death•BBB also protects flies from a high-fat diet and non-pathogenic infections•A mouse tumor model disrupts the protective BBB in an IL-6-dependent manner
Kim et al. use a fly cancer model to uncover a systemic effect of tumors in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model. |
doi_str_mv | 10.1016/j.devcel.2021.08.010 |
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[Display omitted]
•Fly tumors induce paraneoplastic opening of the BBB•BBB permeabilization by tumor-induced JAK/STAT activation accelerates host death•BBB also protects flies from a high-fat diet and non-pathogenic infections•A mouse tumor model disrupts the protective BBB in an IL-6-dependent manner
Kim et al. use a fly cancer model to uncover a systemic effect of tumors in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model.</description><identifier>ISSN: 1534-5807</identifier><identifier>EISSN: 1878-1551</identifier><identifier>DOI: 10.1016/j.devcel.2021.08.010</identifier><identifier>PMID: 34496290</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Biological Transport ; blood-brain barrier ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - physiology ; cancer ; cancer model ; Cells, Cultured ; cytokine ; Cytokines ; Disease Models, Animal ; Drosophila ; Drosophila melanogaster - metabolism ; Drosophila Proteins - metabolism ; Endothelial Cells - metabolism ; IL-6 ; inflammation ; Interleukin-6 - immunology ; Mice ; Mice, Inbred C57BL ; mouse ; Neoplasms - pathology ; paraneoplasia ; Paraneoplastic Syndromes - physiopathology ; Permeability ; Signal Transduction - physiology ; STAT Transcription Factors - metabolism ; tumor</subject><ispartof>Developmental cell, 2021-10, Vol.56 (19), p.2712-2721.e4</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-1904578240cdf17f8efaf24653b21b369627f0a969ac777539000662642801313</citedby><cites>FETCH-LOGICAL-c529t-1904578240cdf17f8efaf24653b21b369627f0a969ac777539000662642801313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.devcel.2021.08.010$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34496290$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Jung</creatorcontrib><creatorcontrib>Chuang, Hsiu-Chun</creatorcontrib><creatorcontrib>Wolf, Natalie K.</creatorcontrib><creatorcontrib>Nicolai, Christopher J.</creatorcontrib><creatorcontrib>Raulet, David H.</creatorcontrib><creatorcontrib>Saijo, Kaoru</creatorcontrib><creatorcontrib>Bilder, David</creatorcontrib><title>Tumor-induced disruption of the blood-brain barrier promotes host death</title><title>Developmental cell</title><addtitle>Dev Cell</addtitle><description>Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities.
[Display omitted]
•Fly tumors induce paraneoplastic opening of the BBB•BBB permeabilization by tumor-induced JAK/STAT activation accelerates host death•BBB also protects flies from a high-fat diet and non-pathogenic infections•A mouse tumor model disrupts the protective BBB in an IL-6-dependent manner
Kim et al. use a fly cancer model to uncover a systemic effect of tumors in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model.</description><subject>Animals</subject><subject>Biological Transport</subject><subject>blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - physiology</subject><subject>cancer</subject><subject>cancer model</subject><subject>Cells, Cultured</subject><subject>cytokine</subject><subject>Cytokines</subject><subject>Disease Models, Animal</subject><subject>Drosophila</subject><subject>Drosophila melanogaster - metabolism</subject><subject>Drosophila Proteins - metabolism</subject><subject>Endothelial Cells - metabolism</subject><subject>IL-6</subject><subject>inflammation</subject><subject>Interleukin-6 - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>mouse</subject><subject>Neoplasms - pathology</subject><subject>paraneoplasia</subject><subject>Paraneoplastic Syndromes - physiopathology</subject><subject>Permeability</subject><subject>Signal Transduction - physiology</subject><subject>STAT Transcription Factors - metabolism</subject><subject>tumor</subject><issn>1534-5807</issn><issn>1878-1551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS1ERUvLN0AoRy4JM_4TOxckVEFBqtRLe7Yc22G9SuLFdlbi2-NqS4ELp7E0896Mf4-QtwgdAvYf9p3zR-vnjgLFDlQHCC_IBSqpWhQCX9a3YLwVCuQ5eZ3zHqoMFbwi54zzoacDXJCb-22JqQ2r26x3jQs5bYcS4trEqSk734xzjK4dkwlrM5qUgk_NIcUlFp-bXcylcd6U3RU5m8yc_Zunekkevny-v_7a3t7dfLv-dNtaQYfS4gBcSEU5WDehnJSfzER5L9hIcWR9vUpOYIZ-MFZKKdgAAH1Pe04VIEN2ST6efA_buHhn_VqSmfUhhcWknzqaoP_trGGnv8ejVgIRBlUN3j8ZpPhj87noJeSKcTarj1vWVEgErhjjdZSfRm2KOSc_Pa9B0I8Z6L0-ZaAfM9CgdM2gyt79feKz6Df0P3_wFdSxAtXZBr9W_iF5W7SL4f8bfgGhsZls</recordid><startdate>20211011</startdate><enddate>20211011</enddate><creator>Kim, Jung</creator><creator>Chuang, Hsiu-Chun</creator><creator>Wolf, Natalie K.</creator><creator>Nicolai, Christopher J.</creator><creator>Raulet, David H.</creator><creator>Saijo, Kaoru</creator><creator>Bilder, David</creator><general>Elsevier Inc</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20211011</creationdate><title>Tumor-induced disruption of the blood-brain barrier promotes host death</title><author>Kim, Jung ; Chuang, Hsiu-Chun ; Wolf, Natalie K. ; Nicolai, Christopher J. ; Raulet, David H. ; Saijo, Kaoru ; Bilder, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-1904578240cdf17f8efaf24653b21b369627f0a969ac777539000662642801313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Biological Transport</topic><topic>blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blood-Brain Barrier - physiology</topic><topic>cancer</topic><topic>cancer model</topic><topic>Cells, Cultured</topic><topic>cytokine</topic><topic>Cytokines</topic><topic>Disease Models, Animal</topic><topic>Drosophila</topic><topic>Drosophila melanogaster - metabolism</topic><topic>Drosophila Proteins - metabolism</topic><topic>Endothelial Cells - metabolism</topic><topic>IL-6</topic><topic>inflammation</topic><topic>Interleukin-6 - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>mouse</topic><topic>Neoplasms - pathology</topic><topic>paraneoplasia</topic><topic>Paraneoplastic Syndromes - physiopathology</topic><topic>Permeability</topic><topic>Signal Transduction - physiology</topic><topic>STAT Transcription Factors - metabolism</topic><topic>tumor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Jung</creatorcontrib><creatorcontrib>Chuang, Hsiu-Chun</creatorcontrib><creatorcontrib>Wolf, Natalie K.</creatorcontrib><creatorcontrib>Nicolai, Christopher J.</creatorcontrib><creatorcontrib>Raulet, David H.</creatorcontrib><creatorcontrib>Saijo, Kaoru</creatorcontrib><creatorcontrib>Bilder, David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Developmental cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Jung</au><au>Chuang, Hsiu-Chun</au><au>Wolf, Natalie K.</au><au>Nicolai, Christopher J.</au><au>Raulet, David H.</au><au>Saijo, Kaoru</au><au>Bilder, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor-induced disruption of the blood-brain barrier promotes host death</atitle><jtitle>Developmental cell</jtitle><addtitle>Dev Cell</addtitle><date>2021-10-11</date><risdate>2021</risdate><volume>56</volume><issue>19</issue><spage>2712</spage><epage>2721.e4</epage><pages>2712-2721.e4</pages><issn>1534-5807</issn><eissn>1878-1551</eissn><abstract>Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities.
[Display omitted]
•Fly tumors induce paraneoplastic opening of the BBB•BBB permeabilization by tumor-induced JAK/STAT activation accelerates host death•BBB also protects flies from a high-fat diet and non-pathogenic infections•A mouse tumor model disrupts the protective BBB in an IL-6-dependent manner
Kim et al. use a fly cancer model to uncover a systemic effect of tumors in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34496290</pmid><doi>10.1016/j.devcel.2021.08.010</doi><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biological Transport blood-brain barrier Blood-Brain Barrier - metabolism Blood-Brain Barrier - physiology cancer cancer model Cells, Cultured cytokine Cytokines Disease Models, Animal Drosophila Drosophila melanogaster - metabolism Drosophila Proteins - metabolism Endothelial Cells - metabolism IL-6 inflammation Interleukin-6 - immunology Mice Mice, Inbred C57BL mouse Neoplasms - pathology paraneoplasia Paraneoplastic Syndromes - physiopathology Permeability Signal Transduction - physiology STAT Transcription Factors - metabolism tumor |
title | Tumor-induced disruption of the blood-brain barrier promotes host death |
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