Brutscher Fabienne, Germani Federico, Hausmann George, Jutz Lena, Basler Konrad
Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
PLoS Biol. 2025 Apr 28;23(4):e3003068. doi: 10.1371/journal.pbio.3003068. eCollection 2025 Apr.
Innate immunity in Drosophila acts as an organismal surveillance system for external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In the absence of oncogenic Ras (RasV12), Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce tumorous overgrowth.
果蝇的先天免疫作为一种针对外部刺激或细胞健康状况的机体监测系统，并触发特定情境下的反应以对抗感染和维持组织内稳态。然而，先天免疫途径的失控激活可能是有害的。在哺乳动物中，先天免疫信号在恶性细胞中常常过度激活，并促进肿瘤进展。果蝇肿瘤模型在发现促进肿瘤发生的途径之间的相互作用方面发挥了重要作用，但对于Toll先天免疫途径是否以及如何与癌基因相互作用却知之甚少。在这里，我们使用果蝇上皮体内模型来研究Toll信号与致癌性Ras之间的相互作用。在没有致癌性Ras（RasV12）的情况下，Toll信号抑制分化并诱导细胞凋亡。相反，在RasV12的背景下，细胞免受细胞死亡的影响，并且背侧蛋白促进细胞存活和增殖以驱动增生。综上所述，我们表明先天免疫活性的组织保护功能可被癌前细胞劫持以诱导肿瘤过度生长。
