The role of JNK signal transduction and inflammation in the development of chronic lung diseases including lung cancer: studies using tailored Drosophila models

Lung cancer is the leading cause of cancer-related mortality. I specifically expressed constitutively active Egfr in the Drosophila airway system and performed a comprehensive phenotypic analysis. Ectopic expression of Egfr induced tumor-like growth of larval tracheal stem cells and thickening of the tracheal epithelium, leading to early death. I found that overexpression of Egfr in larval trachea activated three canonical downstream signaling pathways: MAPK, PI3K/Akt, and JAK/STAT signaling pathways, respectively. I blocked each of the three signaling pathways and found that in this Egfr ectopic expression-induced lung cancer model, the MAPK pathway was mainly involved in proliferation, PI3K/Akt in maintaining cell survival, and JAK/STAT in invasion. Next, I found that JNK activated in the Egfr-induced tumor and blocking JNK rescued tumor-like proliferation and significantly reduced Egfr activation of MAPK, PI3K, and JAK/STAT pathways, while also rescuing Egfr-induced animal death. Specialized overexpression of the receptor PGRP-LC in the airway system activates the IMD pathway. Overexpression of PGRP-LC early in Drosophila development leads to death in the pupal stage in all animals. The airway system of larvae overexpressing PGRP-LC were dissected and I found significant thickening of the tracheal epithelium and shrinking of the T4 and T5 Tracheoblasts, with their location shifted from the dorsal trunk to the secondary bronchi. I found that the tracheoblasts on day 2 of activation were significantly larger than day 1. Next, I identified that IMD-induced phenotypes achieved by activating the following pathways: apoptotic signaling pathway dependent on AP1 and FoxO; migration dependent on STAT; and proliferative dependent on Ets21c, respectively