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Study of Tumor Development Using Drosophila melanogaster Models

Snigdha, Kirti
http://orcid.org/0000-0002-8618-1628
http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591210557481631

Abstract Details

2020, Doctor of Philosophy (Ph.D.), University of Dayton, Biology.
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 an 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 hypothesized that crosstalk between the TLR and TNF pathways in the TME promotes tumor survival and progression through JNK pathway. We observed Drosophila IκB Cactus (TLR component) is upregulated in the tumor cells and downregulating Cactus negatively affect tumor growth (JNK expression) and invasion (JNK target, MMP1 expression). 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. Further, we report Hippo pathway effector, Yki as the ultimate regulator, that transcriptionally regulates Cactus expression which in turn mediates tumor promoting JNK signaling in the tumor cells. We also studied the tumorigenesis in the Drosophila glioma model generated by co-activation of the epidermal growth factor receptor (EGFR) and Phosphatidylinositol 3-kinase (PI3K) pathway. Glioma is an aggressive form of adult brain tumor with poor prognosis due to recurrence of tumor after surgery and radiation treatment. To understand the effect of radiation on glioma, we exposed the glioma to 3.5 Gy of X-ray and observed delayed growth, reduced brain lobe size, and proliferation, yet the exposed larvae did not have any survival advantage and were pupal lethal. Further, the recurrence of glioma after radiation has been associated with presence of glioma stem-like cells. Our collaborator, Dr. I Nakano’s group observed CD109 (Drosophila Tep1) protein is expressed by the surviving tumor cells after radiation treatment which transformed into aggressive and radioresistant tumor cells. Using mammalian and Drosophila models, we confirmed an evolutionarily conserved role of CD109 in glioma progression. Exposure of glioma to ionizing radiation led to transcription of CD109 by activated NF-κB and silencing of CD109 repressed transcription of TAZ. Downregulation of Tep1 in the Drosophila glioma model showed reduction in glioma size, proliferation and reduced Yki expression. Overall, our research helped to unravel the intricate interactions between key signaling pathways that promote tumor progression in an in vivo model. These insights can be extrapolated to mammalian system and further our understanding of tumorigenesis and designing new therapeutics.
Madhuri Kango-Singh, Ph.D. (Advisor)
Amit Singh, Ph.D. (Committee Member)
Mark Nielsen, Ph.D. (Committee Member)
Pothitos Pitychoutis, Ph.D. (Committee Member)
Ichiro Nakano, M.D., Ph.D. (Committee Member)
145 p.
Biology; Biomedical Research; Experiments; Genetics; Immunology; Molecular Biology; Oncology
Cancer; Inflammation; Glioma; Signaling pathway; Yki

Recommended Citations

Citations

  • Snigdha, K. (2020). Study of Tumor Development Using Drosophila melanogaster Models [Doctoral dissertation, University of Dayton]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591210557481631

    APA Style (7th edition)

  • Snigdha, Kirti. Study of Tumor Development Using Drosophila melanogaster Models. 2020. University of Dayton, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591210557481631.

    MLA Style (8th edition)

  • Snigdha, Kirti. "Study of Tumor Development Using Drosophila melanogaster Models." Doctoral dissertation, University of Dayton, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591210557481631

    Chicago Manual of Style (17th edition)

dayton1591210557481631
199
© 2020, all rights reserved.
This open access ETD is published by University of Dayton and OhioLINK.