Methotrexate alleviates chronic inflammation in a Drosophila model

Growth signals and immune responses in cancer typically originate in the same compartments. In early stages of tumor development, inflammatory cells trigger responses against growing cancers. At a molecular level, it is unclear how the innate immune system recognizes tumorigenesis. At later stages, cancer cells resist cell death and evade immune detection, thereby suppressing anti-tumor responses and promoting cancer hallmarks. Often, chronic inflammatory responses become tumor friendly and incline towards tumorigenesis disturbing metabolic signaling, thereby rewiring nutritional supply for cancer growth. The precise connecting link between cancer, nutrition and metabolism remains unclear. Drosophila provides an ideal platform to explore the links between hyperactive immune signaling, defective fat metabolism and pseudotumor formation. Therefore, we examined the effects of methotrexate on these pathophysiological processes in larvae with hyperactive Toll/NF-κB pathway. We determined that both chemical (methotrexate) and genetic [rescue of Ubc9-/- mutants by introducing a wild-type copy of Cactus (negative regulator of the Toll pathway)] interventions alleviated abnormalities associated with Toll/NF-κB hyperactivity and its influence on insulin signaling. Our study underscores drug repurposing studies and provides insights into how immune-metabolic crosstalk rewires inflammation-driven tumorigenesis.