Exploring the role of PI3K signalling in the tumour microenvironment of prostate cancer

Owen, Jasmine 2025. Exploring the role of PI3K signalling in the tumour microenvironment of prostate cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Prostate cancer remains a leading cause of cancer death in men, with outcomes poor for advanced disease, underscoring the need for new treatment strategies. While epithelial PTEN loss is common in tumours, how PTEN expression in surrounding fibroblasts shapes prostate pathology is unclear. To investigate this, we used a combination of laboratory and animal models to specifically delete the PTEN gene from fibroblasts. In mice, this was achieved using a Cre-mediated genetic strategy that allowed PTEN to be depleted in fibroblasts, either alone (to model normal conditions) or alongside PTEN loss in tumour cells (to mimic cancer). We also utilised an in vitro human system using stable PTEN knockdown in established human prostate fibroblasts to test their effects on cancer cells in culture. The biological impact was then quantified using a range of techniques including tissue staining, 3D organoid cultures, livecell imaging, cell sorting, and de-cellularised extracellular matrix (ECM) assays. Across all models, loss of PTEN in fibroblasts altered both the tumour microenvironment and epithelial behaviour. This included increased activity of key growth pathways (such as AKT, mTOR, and ERK), changes to androgen receptor signalling, and extensive remodelling of the ECM. These changes promoted abnormal tissue growth under normal conditions and accelerated cancer progression when combined with epithelial PTEN loss. In vitro studies found that cancer cells responded strongly to changes in the ECM produced by PTENdeficient fibroblasts, whereas isolated paracrine fibroblast signals had more inconsistent effects, thus highlighting the matrix as a key driver of disease. Together, the data supports an ECM-first cascade in which fibroblast PTEN loss drives CAFlike activation, matrix stiffening and reorganisation, and sustained epithelial pro-growth signalling. Collectively, these findings identify fibroblast PTEN as a key regulator of prostate tumorigenesis, suggesting fibroblast PTEN status and stromal signatures as potential biomarkers and supporting further research into the use of combined PI3K/AKT-axis inhibitors with ECM/-targeted strategies to treat prostate cancer.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	28 April 2026
Date of Acceptance:	28 April 2026
Last Modified:	28 Apr 2026 13:10
URI:	https://orca.cardiff.ac.uk/id/eprint/186682

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