Simpson, Benjamin Scott; (2022) Evaluating novel prognostic biomarkers in prostate cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Prostate cancer (PCa) is a major world health issue, killing 358,989 men worldwide each year. Predicting a disease’s likely course (prognosis), is a fundamental question in oncology, and enhanced estimates of disease progression can inform treatment options, improving outcomes. PCa is a disease defined by uncertainty, as many tumours present a minor threat to life, requiring only regular monitoring; others may develop rapidly and become life-threatening. Distinguishing indolent from high-risk tumours remains an ongoing challenge, which may be potentially aided by the use of prognostic biomarkers. This thesis explores three novel prognostic molecular biomarkers which are implicated in aggressive PCa and explores the physiological contexts which lead to their altered states. The first results chapter investigated the upregulation of salt-inducible-kinase 2 (SIK2), which I determined was androgen-regulated in PCa cell lines (LNCaP) and enriched in high Gleason grade PCa tissue collected from the PICTURE trial (assessed via IHC of an in-house tissue microarray). SIK2 exists within a protein network involved in fatty acid biosynthesis and metabolism, and the knockdown of SIK2 in PCa cells altered the expression of key enzymes involved in fatty acid synthesis measured by qPCR. Targeting of SIK2 with therapeutic inhibitors slowed PCa cell growth and reduced the formation of intracellular lipid droplets, further indicating that SIK2 is intrinsically linked to fatty acid biosynthesis in prostate cancer cell line models. The second results chapter assessed the upregulation of syntabulin (SYBU), a kinesin-associated linker protein that becomes overexpressed in PCa tissue compared to benign tissue (assessed via IHC in a tissue microarray), and at an mRNA level was further enriched in tissue arising from prostate cancer metastases. I also found SYBU to be upregulated in tumours that recur rapidly following surgery in three publicly available RNAseq cohorts with long-term follow-up data. Within these cohorts, SYBU mRNA expression independently predicted outcomes following surgery and independently from known clinical and pathological indicators. Immunoprecipitation in PCa cells revealed SYBU to bind kinesin family members, and in transcriptomic data, the upregulation of both proteins was indicative of a highly aggressive clinical phenotype. These results suggest raised SYBU expression may act as a prognostic biomarker if measured within a prostate cancer tumour. Finally, the third results chapter focused on the amplification of the 3q26.31-32 locus, which contains the genes NAALADL2 and TBL1XR1 and is proximal to a genomic fragile site. Following the download of genetic data from multi-omic sequenced tumour tissue from the cancer genome atlas (TCGA) and international cancer genome consortium (ICGC), I demonstrated that copy-number gains in this region frequently occur in up to 50% of primary prostate cancers, occurring more frequently in high Gleason tumours and in men with local invasion. In paired mRNA seq data from the TCGA, gains in NAALADL2/TBL1XR1 resulted in increased expression of both genes and that of neighboring oncogenes, and were associated with transcriptomic features indicative of increased proliferative signaling. Together, these findings enhance the current understanding of the role of these molecules in prostate cancer and the dynamic biological processes they support and open up new avenues of research for potential exploitation as prognostic biomarkers or potential therapeutic targets.

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