Molecular characterization of EGFR-JAK/STAT (EJS) tumours in Drosophila

Thesis

Despite extensive research into the molecular mechanisms of solid tumours, the cellular events facilitating tumour development and their oncogenic transformation are not fully understood. This project aims to characterize the cancer cell biology of solid tumours marked by the concurrent upregulation of the EGFR and JAK/STAT signalling pathways. I capitalised on a similar, previously validated and inducible Drosophila melanogaster tumour model to address this biological question. In addition to the hyperactivation of both oncogenic pathways, EGFR and JAK/STAT (EJS) signallings, the genetic versatility of fruit flies allows for the concomitant manipulation of other biochemical pathways, thus facilitating the identification and functional characterisation of factors required for the malignant transformation. Previous work in the laboratory suggested the involvement of the Drosophila translation initiation factor (eIF3m/Tango7) during the transformation process. My DPhil. has made a systematic functional evaluation of several components that form the eIF3 translation complex in EJS tumours. In my experiments, I have related the appearance of specific oncogenic features to distinct eIF3 components, thus suggesting a functional specificity of the eIF3 subunits rather than the global control of mRNA translation.

In independent investigations, I have uncovered a key role of the transcriptional repressor Ebi in the EJS tumour expansion. My experiments suggest that Ebi acts as a pro-survival factor that reduces the rate of cell death of transformed cells and promotes their proliferation instead. Furthermore, I have revealed that Ebi is proteolytically processed by the Drosophila caspases Dronc and Dcp-1, possibly to facilitate its degradation to reinforce apoptosis induction.

Finally, I have conducted a RNAi-based genetic screen to find modifiers of EJS-tumour growth. To do so, I used a RNAi-fly library for whose gene products FDA approved drugs are available with the aim to validate gene/drug pairs and their impact on EJS-tumours. This screen has identified 32 putative genes relevant to excessive tumour cell growth and larvae developmental delay, which are currently under investigation in the laboratory.

Overall, my project has broadened our comprehension of the molecular basis facilitating the onset and progression of EJS tumours. Importantly, this knowledge could be harnessed to develop future therapeutic strategies.

Authors: Wang, L

• DOI: 10.5287/ora-7qdnevg1k
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: molecular features; malignant transformation; ebi; eIF3; Drosophila melanogaster
• Subjects: Cancer; Drosophila melanogaster