|dc.description.abstract||Prostate cancer is a leading cause of mortality among men worldwide. Targeting the androgen receptor (AR) via androgen deprivation therapy is the first line of treatment against advanced prostate cancer. Nonetheless, the majority of patients develop therapy resistance within 1-3 years. Therefore, there is an imminent need to explore new signalling pathways that could provide novel therapeutic targets.
The Hippo signalling pathway is a master regulator of cell growth, proliferation, and cancer. The transcriptional coactivators of the Hippo pathway, Yes-associated protein (YAP) and its paralog; the transcriptional coactivator with PDZ-binding motif (TAZ) are central in various cancers. The role of YAP/TAZ in prostate cancer (PCa) has gained momentum recently. Recent reports suggest that the central kinases MST1/2 and LAST1/2 inhibit androgenic signalling in prostate epithelial cells. Additionally, exogenous expression of YAP in vitro induces tumorigenesis in prostate epithelial cells. Importantly, YAP and the androgen receptor (AR) colocalise in the nucleus in an androgen dependent manner to promote tumorigenesis. Nonetheless, the exact mechanism of how androgens and AR regulate YAP/TAZ is unexplored. The Hippo-YAP signalling pathway was also reported to exacerbate PCa inflammation via inducing the recruitment of myeloid derived suppressor cells to the PCa niche which modulate immune response evasion. Additional evidence from different cancers and multiple conditions indicates that Hippo-YAP/TAZ signalling is an important regulator of inflammatory processes in non-immune cells. However, our understanding remains limited as to how the Hippo pathway and YAP/TAZ regulate leukocytes in inflammatory and homeostatic settings.
This thesis aimed to understand the mutual regulatory interaction between AR and YAP/TAZ, as well as to understand how YAP/TAZ contribute towards prostate tumorigenesis. Finally, the thesis also describes the development and initial characterisation of an in vivo model system to study the role of YAP/TAZ in regulating tissue resident macrophages and leukocytes.
Herein, androgens are shown to activate YAP/TAZ differentially via AR, where AR regulates YAP translation, while inducing transcription of the TAZ encoding gene, WWTR1. Serum Response Factor (SRF) regulates this AR driven YAP/TAZ activation in a feed forward manner. Importantly, SRF expression correlates with TAZ, CYR61 and CTGF expression in patients with different stages of prostate cancer. Work described in the thesis provide evidence that YAP/TAZ are not essential for sustaining AR activity, however, targeting YAP/TAZ or SRF sensitizes PCa cells to AR inhibition in anchorage independent growth conditions. The findings presented dissect the cellular roles of YAP, TAZ and SRF in prostate cancer cells, which indicates the interplay between these transcriptional regulators and their roles in prostate tumorigenesis and highlights how this insight might be exploited therapeutically.
In the final section of this thesis, Yapfl;fl/Wwtr1fl;fl mice were crossed with mice harbouring the novel CD64.iCre allele, which is a newly developed cre recombinase that targets macrophages independently from other immune cells. Basic characterisation of the CD64.iCre.Yapfl;fl/Wwtr1fl;fl mouse model shows that YAP/TAZ are not essential for macrophages differentiation and proliferation. Nonetheless, preliminary data shows that Yap/Taz loss in macrophages results in lower numbers of neutrophils in liver and lungs, suggesting that Yap/Taz might be regulating neutrophils recruitment to the inflammatory niche.
Initial analysis of the CD64.iCre.Yapfl;fl/Wwtr1fl;fl mouse model provides a solid ground for future experiments to dissect how Yap/Taz regulate macrophages and leukocytes in homeostatic and inflammatory settings.||en