Innate Immune and Kinase Signaling Pathways Regulate Large Extracellular Vesicle Biogenesis and Systemic Tumor–Host Communication

Abstract

Large extracellular vesicles (EVs) are produced primarily by cancer cells as a method of communication with other cells and tissues nearby and at a distance. Despite the established roles of these large EVs in cancer progression and metastasis, much remains unknown about how their formation is regulated and how they interact with the surrounding host systems after release. To address these gaps, we developed the well-characterized Drosophila RasV12, scrib-/- tumor model as a useful system for studying large EV biology. Studying this system in parallel with human cancer cell lines, we identified the innate immune cGAS-STING pathway as a novel regulator of large EV biogenesis acting through JNK and FAK. Interestingly, large EVs produced by tumors are sufficient to induce a systemic immune response in Drosophila through the propagation of STING signaling. A subsequent chemical screen performed in human cancer cells and followed up in the Drosophila RasV12, scrib-/- tumor model identified multiple additional regulators of large EV biogenesis, including LRRK1/2. Altogether, this work establishes a new model for studying large EV biogenesis in vivo, provides additional context for how large EVs interact with the host immune system, and identifies several signaling pathways involved in large EV biogenesis. This research crucially furthers our understanding of the basic biology of large EV biogenesis as well as the roles large EVs play in the context of a whole organism.