Interaction of key inflammatory pathways in the tumor microenvironment in Drosophila cancer models control tumor progression
The interaction between the tumor cells and the surrounding normal cells constitutes the Tumor microenvironment (TME). The Toll-like Receptor (TLR), Jun N-terminal Kinase (JNK), and Tumor Necrosis Factor (TNF) produce inflammatory components in the TME, and are thought to play a critical role in tumor survival and progression. However, the exact nature and mechanism of interactions within the TME remain poorly understood. These core inflammatory pathways are conserved in Drosophila. As 90% of tumors are epithelial in origin, we used a epithelial tumor model in the wing imaginal discs of Drosophila melanogaster to study the interaction of these key inflammatory pathways in the TME. We established a new TME model by creating FLP-out clones of oncogenic forms of Yki or RasV12 in polarity deficient (scribble mutant) cells marked by GFP surrounded by normal cells. These mosaic clones allow us to test changes in intercellular and signaling interactions within the tumor, surrounding its microenvironment and in distant normal cells. We studied the activity of TLR, TNF and JNK pathway using immunohistochemistry. We found that Drosophila IκB Cactus (TLR component) and activated form of JNK (p-JNK) were induced in the tumor cells whereas levels of Drosophila TNF ligand, Eiger were unaffected in both the tumor and the surrounding normal cells. We hypothesized that crosstalk between these key pathways in the TME promotes tumor survival and progression. The genetic epistasis experiments between JNK and TNF revealed that downregulation of the TNF receptors in the tumor does not affect the metastatic abilities of the tumor cells. However, similar experiments between JNK and TLR showed decrease in invasiveness of tumor cells likely due to downregulation of Cactus in the tumor cells. We are currently testing if TLR, TNF and JNK pathways genetically regulate each other or independently affect the TME to control tumor growth. Our research will help to unravel the correlation between inflammatory pathways and tumor progression in an in vivo model.
Madhuri Kango-Singh, Amit Singh
Primary Advisor's Department
Stander Symposium project
"Interaction of key inflammatory pathways in the tumor microenvironment in Drosophila cancer models control tumor progression" (2019). Stander Symposium Projects. 1588.