Only select cell types in an organ display neoplasia when targeted oncogenically. How developmental lineage hierarchies of these cells prefigure their neoplastic propensities is not yet well-understood. Here we show that neoplastic Drosophila epithelial cells reverse their developmental commitments and switch to primitive cell states. In a context of alleviated tissue surveillance, for example, loss of Lethal giant larvae (Lgl) tumor suppressor in the wing primordium induced epithelial neoplasia in its Homothorax (Hth)-expressing proximal domain. Transcriptional profile of proximally transformed mosaic wing epithelium and functional tests revealed tumor cooperation by multiple signaling pathways. In contrast, lgl − clones in the Vestigial (Vg)-expressing distal wing epithelium were eliminated by cell death. Distal lgl − clones, however, could transform when both tissue surveillance and cell death were compromised genetically and, alternatively, when the transcription cofactor of Hippo signaling pathway, Yorkie (Yki), was activated, or when Ras/EGFR signaling was up-regulated. Furthermore, transforming distal lgl − clones displayed loss of Vg, suggesting reversal of their terminal cell fate commitment. In contrast, reinforcing a distal (wing) cell fate commitment in lgl − clones by gaining Vg arrested their neoplasia and induced cell death. We also show that neoplasia in both distal and proximal lgl − clones could progress in the absence of Hth, revealing Hth-independent wing epithelial neoplasia. Likewise, neoplasia in the eye primordium resulted in loss of Elav, a retinal cell marker; these, however, switched to an Hth-dependent primitive cell state. These results suggest a general characteristic of "cells-of-origin" in epithelial cancers, namely their propensity for switch to primitive cell states.

Zika virus (ZIKV) outbreaks pose a massive public health threat in several countries. We have developed an in vivo model to investigate the host-ZIKV interaction in Drosophila. We have found that a strain of ZIKV replicates in wild-type flies without reducing their survival ability. We have shown that ZIKV infection triggers RNA interference, and that mutating Dicer-2, results in enhanced ZIKV load and increased susceptibility to ZIKV infection. Using a flavivirus-specific antibody, we have found that ZIKV is localized in the gut and fat body cells of the infected wild-type flies and results in their perturbed homeostasis. In addition, Dicer-2 mutants display severely reduced insulin activity, which could contribute towards the increased mortality of these flies. Our work establishes the suitability of Drosophila as the model system to study host-ZIKV dynamics, which is expected to greatly advance our understanding of the molecular and physiological processes that determine the outcome of this disease.

To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) of ZIKV-infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes, including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling. To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKVspecific non-structural proteins NS2A, NS2B, NS4A and NS4B. We found that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP. At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with the dominant-negative form of domeless or StatRNAi results in aggravated reduction in eye size, while co-expression of NS4A in HopTuml (also known as hop Tum ) mutant background partially rescues the hop-induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless (Wg) and Cut, and the Notch reporter, NRE-GFP. Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/ STAT signaling, whereas restricted wing growth is induced through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.This article has an associated First Person interview with the first author of the paper.

Lipid droplets (LDs) are lipid-carrying multifunctional organelles, which might also interact with pathogens and influence the host immune response. However, the exact nature of these interactions remains currently unexplored. Here we show that systemic infection of Drosophila adult flies with non-pathogenic Escherichia coli , the extracellular bacterial pathogen Photorhabdus luminescens or the facultative intracellular pathogen Photorhabdus asymbiotica results in intestinal steatosis marked by lipid accumulation in the midgut. Accumulation of LDs in the midgut also correlates with increased whole-body lipid levels characterized by increased expression of genes regulating lipogenesis. The lipid-enriched midgut further displays reduced expression of the enteroendocrine-secreted hormone, Tachykinin. The observed lipid accumulation requires the Gram-negative cell wall pattern recognition molecule, PGRP-LC, but not PGRP-LE, for the humoral immune response. Altogether, our findings indicate that Drosophila LDs are inducible organelles, which can serve as markers for inflammation and, depending on the nature of the challenge, they can dictate the outcome of the infection.

is an outstanding model for studying host antipathogen defense. Although substantial progress has been made in understanding how metabolism and immunity are interrelated in flies, little information has been obtained on the molecular players that regulate metabolism and inflammation in during pathogenic infection. Recently, we reported that the inactivation of thioester-containing protein 2 () and promotes survival and decreases the bacterial burden in flies upon infection with the virulent pathogens and Here, we investigated physiological and pathological defects in mutant flies in response to challenge. We find that and loss-of-function mutant flies contain increased levels of carbohydrates and triglycerides in the presence or absence of infection. We also report that infection leads to higher levels of nitric oxide and reduced transcript levels of the apical caspase-encoding gene in and mutants. We show that and are upregulated mainly in the fat body rather than the gut in -infected wild-type flies and that mutants contain decreased numbers of bacteria in both tissue types. We propose that the inactivation of or in adult flies results in lower levels of inflammation and increased energy reserves in response to , which could confer a survival-protective effect during the initial hours of infection.