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 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.

Automated summary

Cancer patients often die due to systemic physiological perturbations caused by paraneoplastic syndromes, which can be explored in non-mammalian models. In a Drosophila model, malignant-tumor-produced cytokines activate JAK-STAT signaling, particularly in the cells of the blood-brain barrier, leading to premature death. Inhibiting STAT in the BBB rescues barrier function and extends the lifespan of tumor-bearing hosts, highlighting the importance of BBB alterations in tumor-host interactions and other physiological morbidities.