A Drosophila immune response against Ras-induced overgrowth

Abstract

Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12), both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria), which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

The <b><i>Drosophila</i></b> Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing

“…Both groups survived wounding equally well in the long term, in line with previous observations that the absence of a hemolymph clot has limited effects on survival after wounding, even in mutants where immunity is clearly affected [34] . They also both showed a developmental delay due to wounding, similar to that observed after the induction of wounds upon irradiation or in genetically induced wounds as well as in a Drosophila tumor model [35,36] . Strikingly, though, the developmental delay was more pronounced in the mutant, showing that IDGF3 supports a swift recovery after wounding ( fig.…”

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages

“…In Drosophila embryos, hemocytes are required for epidermal wound healing, but this is a non-proliferative process [24]. With respect to tumor models in Drosophila , much of the research to date has focused on the tumor suppressing role of hemocytes and the innate immune response [44–46]. However, a few reports have implicated hemocytes as tumor-promoters in a neoplastic tumor model [40, 47].…”

Damage signals in the insect immune response

“…Expression of active Ras in the salivary glands (using the Beadex driver) induces apoptosis and expression of metalloproteinases and attracts hemocytes. Concomitantly an immune response is activated in the fat body including a set of genes that are activated by microbial intruders as well as a set that is specifically induced in the presence of overgrowing tissue (Hauling et al, 2014). Amongst the induced genes shared by this model and wasp egg infestation a receptor for the import of retinoid precursors into cells (Santa-maria) was significantly upregulated (Wertheim et al, 2005).…”