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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Veröffentlicht in:Developmental cell 2021-10, Vol.56 (19), p.2712-2721.e4
Hauptverfasser: Kim, Jung, Chuang, Hsiu-Chun, Wolf, Natalie K., Nicolai, Christopher J., Raulet, David H., Saijo, Kaoru, Bilder, David
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Sprache:eng
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Zusammenfassung: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.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2021.08.010