EyaHOST, a Modular Genetic System for Investigation of Intercellular and Tumor-Host Interactions in Drosophila melanogaster

Abstract

Cell biology and genetic analysis of intracellular, intercellular and inter-organ interaction studies in animal models are key for understanding development, physiology, and disease. The MARCM technique can emulate tumor development by simultaneous clonal tumor suppressor loss-of-function generation coupled with GAL4-UAS-driven oncogene and marker expression, but the utility is limited for studying tumor-host interactions due to genetic constraints. To overcome this, we introduce EyaHOST, a novel system that replaces MARCM with the QF2-QUAS binary gene expression system under the eya promoter control, unleashing the fly community genome-wide GAL4-UAS driven tools to manipulate any host cells or tissue at scale. EyaHOST generates epithelial clones in the eye epithelium similar to MARCM. EyaHOST-driven RasV12 oncogene overexpression coupled with scribble tumor suppressor knockdown recapitulates key cancer features, including systemic catabolic switching and organ wasting. We demonstrate effective tissue-specific manipulation of host compartments such as neighboring epithelial cells, immune cells, fat body, and muscle using fly avatars with tissue-specific GAL4 drivers. Organ-specific inhibition of autophagy or stimulation of growth-signaling through PTEN knockdown in fat body or muscle prevents cachexia-like wasting. Additionally, we show that RasV12, scribRNAi tumors induce caspase-driven apoptosis in the epithelial microenvironment. Inhibition of apoptosis by p35 expression in the microenvironment promotes tumor growth. EyaHOST offers a general and versatile modular platform for effectively dissecting mechanisms of intercellular and inter-organ communication under physiological or disease conditions, including tumor-host interactions.

Note:
Funding Information: This work was supported by The Norwegian Research Council Toppforsk and Center of Excellence, CanCell grants #262652 and #276070.

Declaration of Interests: The authors have no conflict of interest.

Keywords: Genetic models of disease, TUMOUR-HOST, Cachexia, oncogene, tumor suppressor, Cancer, inter-organ, organ wasting, cell competition, recombinase, clonal analysis, tissue-specific, Drosophila, KD recombinase, QF2, KDRT