Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Julia Cordero, University of Glasgow, UK
- Second opponent: Professor Marco Milan, IRB Barcelona, Spain
- Third member and chair of the evaluation committee: Associate Professor Coen Campsteijn, University of Oslo
Chair of the Defence
Professor II Therese Sørlie, University of Oslo
Principal Supervisor
Associate Professor Tor Erik Rusten, University of Oslo
Summary
Effective cancer therapy requires the understanding of the mechanisms driving tumour development. While mutations in oncogenes and tumour suppressors underlie transformation, tumour progression is also shaped by interactions with local and distant host tissues. These tumour-host interactions critically influence tumour evolution and patient outcome, yet remain incompletely understood. Using the genetic tractability of Drosophila melanogaster, this thesis investigates intrinsic and extrinsic mechanisms of Ras-driven tumourigenesis, one of the most common oncogenic events in human carcinomas. In Article I, we examined how oncogenic Ras engages inflammatory signalling. RNAseq revealed elevated expression of NFκB pathway components. Downregulation of extracellular (PGRP-SA, ModSP) and intracellular (pelle, dorsal) factors reduced tumour growth. Dorsal/NfkB accumulated heterogeneously in tumour cells, particularly at the invasive front, and its silencing impaired invasion. Besides impacting tumour growth, NFκB signalling also regulated tumour survival and differentiation. Overall, we show that Ras hijacks NFκB signalling to sustain multiple cancer hallmarks in vivo. In Article II, we developed EyaHOST, a modular genetic system enabling independent manipulation of tumour and host tissues using a dual recombinase and dual binary expression strategies. EyaHOST recapitulates key features of malignancy, including overgrowth, invasion, misdifferentiation, developmental delay, and systemic wasting. This genetic platform enables the systematic study of non-autonomous gene function in tumour-host interactions. In Article III, we used EyaHOST to investigate interclonal interactions. A reverse genetic screen targeting frequently altered human cancer genes identified oncogenes and tumour suppressors that non-autonomously modulate Ras tumour growth. Genes fell into two groups: interclonal cooperativity and suppression. Notably, disruption of chromatin remodelling complex SWI/SNF in neighbouring cells promoted Ras tumour overgrowth. RNAseq showed that SWI/SNF loss induced a wound-like inflammatory state with increased prostaglandin synthesis and ROS production. Inhibiting these pathways reduced interclonal tumour promotion.
Together, this work advances the understanding of intrinsic and intercellular mechanisms in Ras-driven tumourigenesis and provides new tools to dissect tumour-host interactions.
Additional information
Contact the research support staff.