Stress and immune signaling in a Drosophila tumor model

Cancer cells contain multiple biological alterations that allow them to escape from host surveillance mechanisms. One of the mechanisms that play an essential role in host protection against tumor growth is immunity. However, the immune system may act as a double-edged sword with the potential to both promote and limit tumor growth in a context-dependent manner. This involves both internal and external signaling events such as stress signaling pathways but also communication between cells and/or between cells and the extracellular matrix (ECM). In this thesis, Drosophila melanogaster (the fruit fly) was used to understand the role of two immune-related components, namely the antimicrobial peptide Drosomycin (Drs) and a chitinase-like protein (Idgf3), in a tumor model that involves a tubular organ, namely the salivary glands. In Paper I we investigated Drs function and regulation upon expression of the oncogene RasV12. Initially, Drs was upregulated in the whole SG upon RasV12 expression. However, at the later stage of the tumor, Drs expression was restricted to the proximal region. In contrast, at the distal region, the hallmarks of cancer phenotypes, such as activation of the pro-tumorogenic JNK pathway, adhering immune cells and production of reactive oxygen species (ROS), were elevated. By overexpressing Drs in the distal region, we found that Drs interferes with most cancer hallmarks, including the JNK-pathway, recruitment of immune cells, and ROS production. In Paper II we further characterized the hallmarks of cancer in our model system by addressing external and internal changes and whether Drs may influence them. At the extracellular compartment, we demonstrate the redistribution of the ECM in tumors, recruitment of immune components, including prophenoloxidases (PPOs) and Drs, and identified F-actin as a part of the ECM. Intracellularly, the organs' primary function, secretion, is lost, and the cell’s epithelial organization is disturbed. Drs reversed the majority of these changes. In Paper III we addressed the role of Idgf3 and its effect on external and internal cues. Initially, we found that Idgf3 was induced in the RasV12 salivary glands. Upon knock-down of Idgf3, the cellular organization was restored, and tumor growth was limited. Moreover, Idgf3 expression was correlatively increasing with the progression of the tumor. In line with Paper I, we found a similar correlation with the JNK pathway. Through genetic experiments, we show JNK-mediated regulation of Idgf3 through ROS. By addressing the subcellular localization of Idgf3, we found the protein internalized within enlarged vesicles, which were coated with a cytoskeletal protein, Spectrin. Furthermore, the formation of enlarged vesicles promoted tumor progression through loss of cellular organization. Taken together, the findings presented here emphasize the complexity of the immune system and its function in tumor progression. Further studies are necessary to understand the potential for tumor therapy.