Studying intercellular and interorgan interactions in animal models is key to understanding development, physiology, and disease. We introduce EyaHOST, a system for clonal combinatorial loss- and gain-of-function genetics in fluorescently labeled cells under QF2-QUAS eya promoter control.

Distinct from mosaic analysis with a repressible cell marker (MARCM), it reserves the use of genome-wide GAL4-UAS tools to manipulate any host tissue. EyaHOST-driven Ras V12 overexpression with scribble knockdown recapitulates key cancer features, including systemic catabolic switching and organ wasting.

We demonstrate effective tissue-specific manipulation of host compartments, including homotypic epithelial neighbors, immune cells, fat body, and muscle. Organ-specific inhibition of autophagy or stimulation of growth signaling via PTEN knockdown in fat body or muscle prevents cachexia-like wasting.

Additionally, tumors trigger caspase-driven apoptosis in the neighboring epithelium, and blocking apoptosis with p35 enhances tumor growth. EyaHOST provides a modular platform to dissect mechanisms of intercellular and interorgan communication under physiological or disease conditions.