Bertilsson, H. | bioRxiv Science

bioRxiv2021

The genes controlling normal function of citrate and spermine secretion is lost in aggressive prostate cancer and prostate model systems

BackgroundSecretion of the metabolites citrate and spermine into prostate lumen is a unique hallmark for normal prostate epithelial cells. However, the identity of the genes controlling citrate and spermine secretion remains mostly unknown despite their obvious relevance for progression to aggressive prostate cancer. Materials & MethodsIn this study, we have correlated simultaneous measurement of citrate/spermine and transcriptomics data. We have refined these gene correlations in 12 prostate cancer cohorts containing 2915 tissue samples to create a novel gene signature of 150 genes connected with citrate and spermine secretion. We further explored the signature in public data, interrogating over 18 000 samples from various tissues and model systems, including 3826 samples from prostate and prostate cancer. ResultsIn prostate cancer, the expression of this gene signature is gradually lost in tissue from normal epithelial cells through PIN, low grade (Gleason <= 7), high grade cancer (Gleason >= 8) and metastatic lesions. The accuracy of the signature is validated by its unique enrichment in prostate compared to other tissues, and its strong enrichment in epithelial tissue compartments compared to stroma. Several zinc-binding proteins that are not previously investigated in the prostate are present in the gene signature, suggesting new mechanisms for controlling zinc homeostasis in citrate/spermine secretion. However, the absence of the gene signature in all common prostate normal and cancer cell-lines, as well as prostate organoids, underlines the challenge to study the role of these genes during prostate cancer progression in model systems. ConclusionsA large collection of transcriptomics data integrated with metabolomics identifies the genes related to citrate and spermine secretion in the prostate, and show that the expression of these genes gradually decreases on the path towards aggressive prostate cancer. In addition, the study questions the relevance of currently available model systems to study metabolism in prostate cancer development.

bioinformatics↗

bioRxiv2017

Cholesterol Synthesis Pathway Genes in Prostate Cancer are consistently downregulated when tissue confounding is minimized.

The relationship between cholesterol and prostate cancer has been extensively studied for decades, where high levels of cellular cholesterol are generally associated with cancer progression and less favorable outcomes. However, the role of in vivo cellular cholesterol synthesis in this process is unclear, and data on the transcriptional activity of cholesterol synthesis pathway genes in tissue from prostate cancer patients are inconsistent. A common problem with cancer tissue data from patient cohorts is the presence of heterogeneous tissue which confounds molecular analysis of the samples. In this study we present a method to minimize systematic confounding from stroma tissue in seven patient cohorts consisting of 1713 prostate cancer and 230 normal tissue samples. When confounding was minimized, differential gene expression analysis over all cohorts showed robust and consistent downregulation of nearly all genes in the cholesterol synthesis pathway. Additional analysis also identified cholesterol synthesis as the most significantly altered metabolic pathway in prostate cancer. This surprising observation is important for our understanding of how prostate cancer cells regulate cholesterol levels in vivo. Moreover, we show that tissue heterogeneity explains the lack of consistency in previous expression analysis of cholesterol synthesis genes in prostate cancer.

cancer biology↗