Affiliations: 1) MRC London Institute of Medical Sciences, UK; 2) Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
Keywords: h. tumorigenesis; d. intestinal stem cells
Cancer risk, type and progression varies 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.
The Drosophila midgut, analogous to the human small intestine, is a highly sexually dimorphic organ. As well as changes in metabolism, size and shape of the midgut, the intestinal stem cells (ISCs) that replenish the intestinal epithelium of adult flies divide more in females than males. After mating the female ISCs proliferate further: the midgut undergoes extensive remodelling, changing its lipid metabolism and increasing midgut size to prepare for energy-intensive egg laying.
It has been previously reported that females produce more proliferative NotchRNAi and RasG12VAPC-/- midgut tumours than males. We have confirmed this sexual dimorphism is also present in Hippo pathway tumours induced by activation of Yorkie (Yki3SA)or downregulation of Warts (WtsRNAi).
Both NotchRNAiand RasG12VAPC1RNAitumours show an enhancement in proliferation after mating in females, reflecting the mated females larger and more proliferative midguts. Unexpectedly, two genetically distinct Hippo pathway tumours (Yki3SA and WtsRNAi) instead have (i) unusually high proliferation in virgin females, and (ii) lack of enhanced proliferation in response to mating. This suggests that differences in Hippo signalling may normally contribute to the reproductive differences in intestinal proliferation.
This demonstrates that different midgut tumour models respond differently to sex and reproductive status. Next we will explore the underlying molecular mechanisms, focusing on the Hippo pathway and metabolism more broadly.