EyaHOST, a modular genetic system for investigation of intercellular and tumor-host interactions in Drosophila melanogaster.
| Title: | EyaHOST, a modular genetic system for investigation of intercellular and tumor-host interactions in Drosophila melanogaster. |
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| Authors: | Teles-Reis J; Jain A; Liu D; Khezri R; Micheli S; Gomez AA; Dillard C; Rusten TE |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 11. Date of Electronic Publication: 2024 Sep 11. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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 Ras V12 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 neighbouring 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 Ras V12 , scrib RNAi tumors induce caspase-driven apoptosis in the epithelial microenvironment. Inhibition of apoptosis by p35 expression in the microenvironment promotes tumor growth. EyaHOST offers a versatile modular platform for dissecting tumor-host interactions and other mechanisms involving intercellular and inter-organ communication in Drosophila .; Highlights: * eyes absent , eye disc-specific enhancer drives clonal KD recombinase flip-out activated QF2 expression in the larval eye epithelium for simultaneous QUAS-driven gain and loss-of-function analysis of gene function. *Clones are visualized by QUAS-tagBFP or QUAS-eGFP facilitating analysis of existing fluorescent reporters.*The GAL4-UAS system and existing genome-wide genetic tools are released to independently manipulate any cell population in the animal for cell biology, intercellular or inter-organ analysis for developmental, physiological, or disease model analysis.*Fly avatars for tumor-host interaction studies with multiple organs allow live monitoring and manipulation of tumors and organs in translucent larva. |
| Comments: | Update in: Cell Rep Methods. 2025 Nov 17;5(11):101220. doi: 10.1016/j.crmeth.2025.101220.. (PMID: 41192417) |
| Entry Date(s): | Date Created: 20240924 Date Completed: 20251112 Latest Revision: 20251118 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11418954 |
| DOI: | 10.1101/2024.09.06.611647 |
| PMID: | 39314415 |
| Database: | MEDLINE |
Journal Article; Preprint