jgreis

• Dillard, Caroline Marie Claude; Reis, Jose Gerardo Belem Teles Roque Dos; Jain, Ashish; Antunes, Marina Manuel Goncalves; Duran, Paula Ruiz & Qi, Yanyan [Show all 9 contributors for this article] (2025). NF-κB signaling driven by oncogenic Ras contributes to tumorigenesis in a Drosophila carcinoma model. PLoS Biology. ISSN 1544-9173. 23(4), p. 1–24. doi: 10.1371/journal.pbio.3002663. Full text in Research Archive Show summary

  Cancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis. Drosophila melanogaster tumor models are increasingly recognized as models to inform conserved molecular mechanisms of tumorigenesis with both local and systemic effects of cancer. Although initial discoveries of the Toll-NFκB signaling pathway in development and immunity were pioneered in Drosophila , limited information is available for its role in cancer progression. Using a well-studied cooperative Ras V12 -driven epithelial-derived tumor model, we here describe functions of Toll-NF-κB signaling in malignant Ras V12 , scrib - tumors. The extracellular Toll pathway components ModSP and PGRP-SA and intracellular signaling Kinase, Pelle/IRAK, are rate-limiting for tumor growth. The Toll pathway NFκB protein Dorsal as well as cactus/I κΒ show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic Ras V12 , and not loss of scribble, confers increased expression and heterogenous distribution of two Dorsal isoforms, DorsalA and DorsalB, in different tumor cell populations. Mechanistic analyses demonstrates that Dorsal, in concert with the BTB-transcription factor Chinmo, drives growth and malignancy by suppressing differentiation, counteracting apoptosis, and promoting invasion of Ras V12 , scrib - tumors.

• Reis, Jose Gerardo Belem Teles Roque Dos; Jain, Ashish; Liu, Dan; Khezri, Rojyar; Antunes, Marina Manuel Goncalves & Micheli, Sofia [Show all 9 contributors for this article] (2025). EyaHOST, a modular genetic system for investigation of intercellular and tumor-host interactions in Drosophila melanogaster. Cell Reports Methods. 5(11), p. 1–16. doi: 10.1016/j.crmeth.2025.101220. Full text in Research Archive Show summary

  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 RasV12 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.

• Khezri, Rojyar; Holland, Petter; Schoborg, Todd Andrew; Abramovich, Ifat; Takats, Szabolcs & Dillard, Caroline Marie Claude [Show all 21 contributors for this article] (2021). Host autophagy mediates organ wasting and nutrient mobilization for tumor growth. EMBO Journal. ISSN 0261-4189. 40(18). doi: 10.15252/embj.2020107336. Full text in Research Archive Show summary

  During tumor growth—when nutrient and anabolic demands are high—autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12; scrib−/− tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

• Dillard, Caroline Marie Claude; José, Gerardo Teles Reis, & Rusten, Tor Erik (2021). RasV12 scrib−/− tumors: A cooperative oncogenesis model fueled by tumor/host interactions. International Journal of Molecular Sciences. ISSN 1661-6596. 22:8873, p. 1–27. doi: 10.3390/ijms22168873. Full text in Research Archive Show summary

  The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic RasV12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the RasV12; scrib−/− tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell–cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression.

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