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Anti-tumor effects of antimicrobial peptides, targets of the innate immune system, against hematopoietic tumors in Drosophila mxc mutants

ABSTRACT: The innate immune response is the first line of defence against microbial infections. In Drosophila, two major immune pathways induce the synthesis of antimicrobial peptides (AMPs) in the fat body. Recently, it has been reported that certain cationic AMPs exhibit selective cytotoxicity against human cancer cells. However, not much is known about their anti-tumour effects. Drosophila mxc(mbn1) mutants exhibit malignant hyperplasia in a larval haematopoietic organ called the lymph gland (LG). Here, using RNA-Seq analysis, we found that many immunoresponsive genes, including AMP genes, were up-regulated in the mutants. Down-regulation of these pathways by either a Toll or an imd mutation enhanced the tumour phenotype of the mxc mutants. Conversely, ectopic expression of each of five different AMPs in the fat body significantly suppressed the LG hyperplasia phenotype in the mutants. Thus, we propose that the Drosophila innate immune system can suppress the progression of haematopoietic tumours by inducing AMP gene expression. Overexpression of any one of these five AMPs resulted in enhanced apoptosis in the mutant LGs, while no apoptotic signals were detected in the controls. We observed that two AMPs, Drosomycin and Defensin, were taken up by circulating haemocyte-like cells, which were associated with the LG regions showing reduced cell-to-cell adhesion in the mutants. On the other hand, another AMP, Diptericin, was directly localised at the tumour site without intermediating haemocytes. These results indicate that AMPs have a specific cytotoxic effect that enhance apoptosis exclusively in the tumour cells.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE121551 | GEO | 2019/06/12

REPOSITORIES: GEO

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Project description:Hematological disorders result in perturbed homeostasis of the blood system. However, a comprehensive understanding of how physiological and genetic mechanisms regulate blood cell precursor maintenance and differentiation is lacking. Owing to simplicity and ease of genetic analysis, the Drosophila melanogaster lymph gland (LG) is an excellent model to study hematopoiesis. The LG is a multi-lobed structure compartmentalized into precursor and differentiation zones whose geography and identity is regulated by multiple signalling pathways. While additional molecular and functional subtypes are expected there is a paucity of information on gene expression and regulation of hemocyte homeostasis. Hence, we quantitatively analyzed the LG proteome under conditions that maintain precursors or promote their differentiation in vivo, by perturbing expression of Asrij, a conserved endosomal regulator of hematopoiesis. Although technically demanding, we pooled samples obtained from 1500 larval dissections per genotype and using iTRAQ quantitative proteomics, determined the relative expression levels of polypeptides in Asrij knockout (KO) and overexpressing (OV) LGs in comparison to wild type (control). Mass spectrometry data analysis showed that at least 6.5% of the Drosophila proteome is expressed in wild type LGs.Of 2,133 proteins identified, 780 and 208 proteins were common to the previously reported cardiac tube and hemolymph proteomes, respectively, resulting in the identification of 1238 proteins exclusive to the LG. Perturbation of Asrij levels led to differential expression of 619 proteins, of which 23% have human homologs implicated in various diseases. Proteins regulating metabolism, immune system, signal transduction and vesicle-mediated transport were significantly enriched. Immunostaining of representative candidates from the enriched categories and previous reports confirmed 75% of our results and validated the LG proteome. Our study provides, for the first time, an in vivo proteomics resource for identifying novel regulators of hematopoiesis that will also be applicable to understanding vertebrate blood cell development.

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Anti-tumor effects of antimicrobial peptides, targets of the innate immune system, against hematopoietic tumors in Drosophila mxc mutants

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