Abstract
To avoid over- or under-treatment of primary prostate tumours, there is a critical need for molecular signatures to discriminate indolent from aggressive, lethal disease. Reprogrammed energy metabolism is an important hallmark of cancer, and abnormal metabolic characteristics of cancers have been implicated as potential diagnostic/prognostic signatures. While genomic and transcriptomic heterogeneity of prostate cancer is well documented and associated with tumour progression, less is known about metabolic heterogeneity of the disease. Using a panel of high fidelity patient-derived xenograft (PDX) models derived from hormone-naïve prostate cancer, we demonstrated heterogeneity of expression of genes involved in cellular energetics and macromolecular biosynthesis. Such heterogeneity was also observed in clinical, treatment-naïve prostate cancers by analyzing the transcriptome sequencing data. Importantly, a metabolic gene signature of increased one-carbon metabolism or decreased proline degradation was identified to be associated with significantly decreased biochemical disease-free patient survival. These results suggest that metabolic heterogeneity of hormone-naïve prostate cancer is of biological and clinical importance and motivate further studies to determine the heterogeneity in metabolic flux in the disease that may lead to identification of new signatures for tumour/patient stratification and the development of new strategies and targets for therapy of prostate cancer.
Highlights
Prostate cancer is a clinically heterogeneous disease covering a wide variety of phenotypes, ranging from indolent disease to aggressive lethal disease
A panel of patientderived xenograft (PDX) models of hormone-naïve prostate cancers demonstrates heterogeneity of expression of genes involved in energy metabolism and recapitulates metabolic heterogeneity of clinical samples
A panel of 11 well-characterized LTL (Living Tumour Laboratory) prostate cancer PDX-models that are derived from hormone-naïve prostate cancer tissues, presents a unique opportunity for focusing on metabolic alterations in prostate cancer cells by analyzing human genes in vivo [19]
Summary
Prostate cancer is a clinically heterogeneous disease covering a wide variety of phenotypes, ranging from indolent disease to aggressive lethal disease. Prostate cancers have abnormal metabolisms for citrate and choline [1315] and are characterized by increased levels of cholinecontaining compounds (ChoCCs). These compounds have been linked to increased cell proliferation and survival [16]. Tracing metabolites with (11C)- and (18F)labeled choline derivative-based PET and PET/CT scans is increasingly used in the clinic Together, these glucose and choline-based imaging studies demonstrated the metabolic heterogeneity of clinical prostate cancer [17, 18]. These glucose and choline-based imaging studies demonstrated the metabolic heterogeneity of clinical prostate cancer [17, 18] It is not clear whether prostate cancer subtypes are metabolically different, or whether metabolic heterogeneity (intra-tumoural and inter-tumoural) can affect tumour response to treatment. A better understanding of metabolic heterogeneity of prostate cancer at a molecular level will provide mechanistic insights into disease progression and may lead to identification of novel diagnostic/prognostic signatures for stratification of patients’ prostate cancers
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