Investigation of altered cell-cell interactions and signaling mechanisms in Drosophila tumor models

Date of Award

2016

Degree Name

Ph.D. in Biology

Department

Department of Biology

Advisor/Chair

Advisor: Madhuri Kango-Singh

Abstract

Tumors develop as a result of mutations in multiple genes which typically include tumor suppressor genes, or proto-oncogenes. These mutations promote abnormal proliferation and evasion of cell death resulting in tumor progression and metastasis. Solid tumors arise and grow amongst normal cells. Therefore, they are constantly in communication with their normal neighbors. The intercellular signaling interactions between emerging cancer cells and their neighbors have significant impact on tumor growth. We used scribble loss of function as a model to study altered intercellular interactions between mutant cells and their neighbors in Drosophila melanogaster. scribble⁻/⁻ cells form neoplastic tumors in a homotypic environment. In contrast, they are eliminated when surrounded by normal cells. However, their growth potential can be enhanced in the presence of secondary growth promoting mutations. We discovered that altering the genetic background ofscribble⁻/⁻ cells results in alterations in intercellular interactions that underlie their growth potential. We found that scribble⁻/⁻ has context dependent effects on proliferation, apoptosis, differentiation, adhesion and metastasis that is linked to tumor growth and progression. Amongst all the genetic combinations we studied only overexpression of Ras V¹² in scribble⁻/⁻ cells gives rise to neoplastic tumors. All other growth promoting modifiers enhanced the survival of scribble⁻/⁻ cells without causing neoplasia suggesting that additional growth promoting mutations are required to cause their aggressive growth. We discovered a novel tumor specific signaling network where Wingless acts as a major driver of aggressive growth upstream of Dronc to induce Jun N-terminal Kinase-Yorkie signal amplification positive feedback loop. The organization of this signaling hierarchy is further important to promote invasiveness of Ras V¹², scribble⁻/⁻ tumors. As a side project, we also tested if the mechanism of aggressive growth identified in the epithelial tumors was conserved in tumors of other cell type such as glioma. Using previously established glioma model generated by overexpression of Ras V¹² and Phosphatidylinositol-4,5-bisphosphate 3-kinase pathway, we discovered that at least 2 signaling proteins (Wingless and Yorkie) are induced in glioma and may underlie glioma pathogenesis. We further show that during gliomagenesis, over proliferation of glial cells occurs due to increase in number of progenitor cells. Lastly, we established that Forkhead Domain 59 mediated regulation of Aldehyde Dehydrogenase is an evolutionarily conserved regulatory mechanism required for aggressive glioma growth in flies. Forkhead Box D1 (vertebrate homolog of Forkhead Domain 59) mediated regulation of Aldehyde Dehydrogenase 1A3 was identified in Dr. I Nakano's lab (our collaborator) as a novel mechanism via which Mesenchymal Glioma Stem Cells maintain their phenotype and participate in aggressive growth. Taken together, our research identified novel key signaling network that promotes tumorigenesis in Drosophila epithelial models by altering intercellular interactions. We further show that this signaling network may also be conserved in glioma model. Our results can be extrapolated to other tumor models providing helpful insights into designing novel therapeutic approaches.

Keywords

Tumors Growth, Cell interaction, Growth factors, Biology, Drosophila, Tumor, Intercellular interactions, Neoplasia, Oncogenic Ras, Scribble, Hippo pathway

Rights Statement

Copyright © 2016, author

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