Exploring how Drosophila midgut tumours respond to sex and reproduction
File(s)
Author(s)
Strachan, Emily Ophelia
Type
Thesis
Abstract
Cancer risk, type and progression vary with sex, due to a range of genetic, hormonal and behavioural factors. Post pregnancy, this is modulated further due to changes in hormones, growth factors and the immune system. However, these factors are often overlooked in experimental disease models. Here I use the fruit fly Drosophila melanogaster as a model system to investigate how sex and reproduction affect tumour progression.
I compare several different genetic tumours generated in the progenitor cells of the adult fly midgut and show how sex and reproductive status affects tumour proliferation. I show tumours induced by simultaneous overexpression of oncogenic Ras (RasG12V) and downregulation of tumour suppressor Apc (ApcRNAi) proliferate more in mated females. Unexpectedly, I found that the Hippo pathway midgut tumours, induced by overexpression of a constitutively active oncogene yorkie (yki3SA) or downregulation of tumour suppressor warts (wtsRNAi), behave differently in response to sex and reproduction.
Unlike RasG12V ApcRNAi tumours, Hippo pathway tumours exhibited unusually high proliferation in virgin females and lose many of their transcriptional post-mating differences. Furthermore, I observe that male-biased sugar metabolism is suppressed in highly proliferative yki3SA male tumours, but not in non-proliferative wtsRNAi male tumours. I investigate the expression of several sexually dimorphic sugar enzymes and show their expression changes in both gut region and cell type in tumours. I also show that these male-biased sugar genes are downregulated in healthy female flies after mating.
Thus, I demonstrate that the tumour response to sex and reproductive status is dependent on genetic model, with different Hippo pathway tumours losing dependency on sex and reproductive cues. This reveals a new potential function for the Hippo pathway in the adult midgut in modulating post-mating remodelling. These findings highlight the importance of considering tumour genotype, sex and reproductive status when studying cancer.
I compare several different genetic tumours generated in the progenitor cells of the adult fly midgut and show how sex and reproductive status affects tumour proliferation. I show tumours induced by simultaneous overexpression of oncogenic Ras (RasG12V) and downregulation of tumour suppressor Apc (ApcRNAi) proliferate more in mated females. Unexpectedly, I found that the Hippo pathway midgut tumours, induced by overexpression of a constitutively active oncogene yorkie (yki3SA) or downregulation of tumour suppressor warts (wtsRNAi), behave differently in response to sex and reproduction.
Unlike RasG12V ApcRNAi tumours, Hippo pathway tumours exhibited unusually high proliferation in virgin females and lose many of their transcriptional post-mating differences. Furthermore, I observe that male-biased sugar metabolism is suppressed in highly proliferative yki3SA male tumours, but not in non-proliferative wtsRNAi male tumours. I investigate the expression of several sexually dimorphic sugar enzymes and show their expression changes in both gut region and cell type in tumours. I also show that these male-biased sugar genes are downregulated in healthy female flies after mating.
Thus, I demonstrate that the tumour response to sex and reproductive status is dependent on genetic model, with different Hippo pathway tumours losing dependency on sex and reproductive cues. This reveals a new potential function for the Hippo pathway in the adult midgut in modulating post-mating remodelling. These findings highlight the importance of considering tumour genotype, sex and reproductive status when studying cancer.
Version
Open Access
Date Issued
2023-12-30
Date Awarded
2024-05-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Hirabayashi, Susumu
Miguel-Aliaga, Irene
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)