The maintenance of homeostasis in the intestinal epithelium of Drosophila melanogaster

Naszai, Mate (2018) The maintenance of homeostasis in the intestinal epithelium of Drosophila melanogaster. PhD thesis, University of Glasgow.

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Adult stem cells are undifferentiated cells that can multiply by cell division to self-renew and replenish dying or damaged cells. Stem behaviour is under the control of a plethora of evolutionarily conserved signalling pathways. A better understanding of these pathways will not only improve our knowledge of stem cell biology, but will also aid our understanding of fundamental health and disease associated processes, such as tissue regeneration and cancer.

During my PhD thesis work I have used the fruit fly Drosophila melanogaster to characterise four independent genetically engineered models of colorectal cancer and to untangle the role of the Ras-like GTPase RalA in stem cell biology.

Cancer development and progression involves a complex interplay between multiple tumour intrinsic and extrinsic factors. In order the gain a better understanding of these factors we used four established genetic models of colorectal cancer (CRC), induced by the loss of the tumour suppressor Adenomatous polyposis coli (Apc) or the overexpression of the oncogene RasV12, Src or the inflammatory cytokine homologue, Upd. We have identified common and context-dependent features of intestinal hyperplasia that not only support the validity of Drosophila to model CRC, but also as a paradigm to achieve additional insights into the involvement of immunity and metabolic rewiring in cancer.

Since their initial discovery, Ral GTPases have emerged as effectors of Ras signalling with a potential role in cancer. Yet, a comprehensive assessment of Ral’s function in vivo was lacking. In collaboration with our colleagues at the Beatson Institute, we have demonstrated that Ral GTPases are dispensable for steady-state homeostatic maintenance of the Drosophila and mouse intestine, but are required for tissue regeneration following damage. This function of Ral GTPases is mediated through stem cell-autonomous modulation of key, conserved proliferative signalling pathways, Wnt and EGFR.

The data presented in this thesis demonstrates the conservation of key aspects of cancer biology and identifies new functions of Ral GTPases and Wnt and EGFR signalling with direct relevance for human biology.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Supervisor's Name: Cordero, Dr. Julia B.
Date of Award: 2018
Embargo Date: 4 January 2022
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:2018-39058
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 04 Jan 2019 11:31
Last Modified: 16 Feb 2020 16:51
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