Delineating how PI3K/PTEN oncogenic signalling contributes to prostate cancer

Mullen, Manisha 2021. Delineating how PI3K/PTEN oncogenic signalling contributes to prostate cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

In 2020, an estimated 19.3 million new cancer cases were diagnosed, 7.3 % of which were cancer of the prostate. It is evident that the development of prostate tumours is highly dependent on the acquisition of genomic alterations and recent work has identified the potential to stratify patients for therapies based on their mutational status. The phosphatidylinositol-3-kinase (PI3K) signalling cascade is frequently activated in prostate cancer, promoting tumour growth and survival. Additionally, the PI3K pathway has been shown to mediate resistance to androgen-deprivation therapy (ADT), leading to lethal and currently untreatable castrate-resistant prostate cancer (CRPC), thus a key clinical challenge faced in the clinic is how to effectively target the PI3K pathway. Previous work in the lab has identified that Pten loss and Pik3ca activation, that frequently drive PI3K signalling in patients with prostate cancer, cause distinct prostate cancer pathologies and can cooperate to accelerate tumorigenesis and CRPC transition in vivo, suggesting that different genetic drivers within the PI3K pathway can mediate distinct signalling events. To delineate the mechanisms in which oncogenic Pik3ca (Pik3ca+/H1047R) and Pten loss (Ptenfl/fl) in the prostate drive tumorigenic processes, this project utilised RNA-Sequencing (RNA-Seq) and ensemble gene set enrichment pathway analysis (eGSEA). In the intact (uncastrated) setting, we identified significant upregulation of NF-κB transcription factors, pathway mediators and transcriptional targets in Pten-deficient prostate cancer relative to Pik3ca-activated prostate tumours. Our bioinformatic based findings were further validated in Pten-deficient in vitro and ex vivo models of prostate cancer, highlighting the NF-κB pathway as a PI3K-independent avenue for therapeutic intervention in patients with PTEN-null prostate cancer. Furthermore, to determine whether Pten loss in fibroblasts could additionally drive tumorigenic processes in the prostate, this project examined the phenotype of Col1a2CreER(T2) wild-type, Pten+/fl and Ptenfl/fl transgenic mouse prostates. We observed focal prostate hyperplasia within all prostate lobes following heterozygous and homozygous loss of fibroblast cell PTEN, indicating that PTEN loss in either epithelial or stromal cells of the prostate can disrupt normal tissue homeostasis. These findings highlight the need to further understand how PI3K/PTEN signalling coordinates tumour�stroma interactions during prostate tumorigenesis, which may uncover new therapeutic targets and/or predictive biomarkers.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	24 May 2022
Date of Acceptance:	24 May 2022
Last Modified:	06 Jan 2024 03:38
URI:	https://orca.cardiff.ac.uk/id/eprint/149972

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