A fatty acid metabolism enzyme drives prostate cancer aggressiveness and may help to predict poor clinical outcome
A recent publication in Oncogene by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) provides insights into how the enzyme ECI1 contributes to tumour aggressiveness by increasing cell growth, motility, and metastatic spread. High levels of ECI1 detected in patient tumour samples were associated with poor clinical outcome after surgery and may help to identify men with aggressive prostate cancer.
Not all prostate cancer is the same. Some tumours remain relatively harmless, while others have the potential to become life-threatening. Current tests are not able to distinguish precisely between these two types of tumours. It is often difficult to identify an optimal therapeutic approach that maximizes the chance of curing aggressive disease while avoiding unnecessary treatment of slow-growing tumours. Unfortunately, around 25-30% of men experience a relapse after prostate cancer surgery, and the treatment options for advanced prostate cancer remain limited.
“Our laboratory aims to understand the functional impacts of genomic alterations found in prostate cancer, and to derive new prognostic biomarkers to distinguish aggressive from indolent, slow-growing tumours,” said Jacques Lapointe, MD, PhD, a scientist in the Cancer Research Program at the RI-MUHC and senior author of this study. “While mining our previous genomic data, we observed high levels of ECI1 enzyme transcripts in a subgroup of aggressive prostate tumours. These tumours harbored a genomic alteration ─ more DNA copies ─ at the region of chromosome 16, which encodes ECI1. We knew that ECI1 was involved with fatty acid metabolism, but did not know whether its high level of expression was linked to prostate cancer aggressiveness.”
“We demonstrated with in vitro experiments that prostate cancer cells expressing high level of ECI1 grew more, moved faster, and generated more energy than those with low levels of this enzyme,” adds Yogesh M. Bramhecha, PhD, first author of the publication and a doctoral trainee with Dr. Lapointe at the time of this work.
Working with data from a cohort of 332 patients treated by radical prostatectomy at the McGill University Health Centre, the researchers also showed that the high level of ECI1 enzyme detected in tumour samples was associated with an increased risk of cancer recurrence and metastasis after surgery.
“We also needed to assess whether the effects of ECI1 observed in prostate cancer cells in vitrowould translate in vivo,” says Karl-Philippe Guérard, M.Sc., second author on the paper and a research associate in Dr. Lapointe’s laboratory. “We modified the prostate cancer cells overexpressing ECI1 and tracked them in mouse prostate using bioluminescence live imaging. We rapidly saw that ECI1 overexpressing cells formed larger tumours in the prostate and were more likely to spread to distant organs than were the control cells.”
“It is remarkable that the overexpression of a single enzyme involved in fatty acid metabolism was enough to enhance tumour aggressiveness,” adds Dr. Lapointe, who is also an associate professor in the Faculty of Medicine and Health Sciences at McGill University. “We know that prostate cancer relies heavily on fatty acids as source of energy, and ECI1 may provide the metabolic flexibility required for prostate cancer cells to thrive. Thus, EC1 and similar metabolic enzymes may be considered as a target for future novel therapeutic treatments.”
About the study
The study, called Fatty Acid Oxidation Enzyme Δ3, Δ2-enoyl-CoA isomerase 1 (ECI1) Drives Aggressive Tumour Phenotype and Predicts Poor Clinical Outcome in Prostate Cancer Patients, was conducted by Yogesh M Bramhecha, Karl-Philippe Guérard, Étienne Audet-Walsh, Shaghayegh Rouzbeh, Ola Kassem, Erwan Pernet, Eleonora Scarlata, Lucie Hamel, Fadi Brimo, Maziar Divangahi, Armen G Aprikian, Simone Chevalier, Vincent Giguère, and Jacques Lapointe.
The authors thank the Small Animal Imaging Labs platform of the RI-MUHC. This research was made possible with the financial support of the U.S. Department of Defense, Prostate Cancer Canada, the Fonds de Recherche du Québec-Santé, the Canadian Institutes of Health Research, McGill Division of Urology studentships, and 100 Days Across Canada Urology Studentship Program on Prostate Cancer.