This week we profile a recent publication in European Urology from the
laboratory of Dr. Xuesen Dong (pictured) at the Vancouver Prostate Centre.
Can you provide a brief overview of your lab’s current research focus?
The research focus of our lab is on the late stage lethal prostate cancers, called castrate-resistant prostate cancers (CRPC). These are recurring tumours after androgen receptor (AR) pathway inhibitor treatments. We study the molecular mechanisms by which prostate cancer cells progress from being androgen sensitive to androgen independent. Particularly, we focus on how alternative RNA splicing antagonizes AR pathway inhibitors to confer cancer phenotypic plasticity, thereby therapy resistant. Information collected from these studies will help us not only identify biomarkers of CRPC, but also design therapeutic strategies to treat CRPC patients.
Three specific projects are ongoing. We study the biosynthesis of RNA splice variants of the androgen receptor by prostate cancer cells to generate AR-v7 and AR circular RNAs. These AR variants are induced by AR pathway inhibitors, and have been demonstrated, or are being studied, as diagnostic or prognostic biomarkers of prostate cancer. We study the RNA splicing factor SRRM4, which transforms prostate adenocarcinoma into aggressive therapy-resistant neuroendocrine prostate cancers (NEPC) through re-programming RNA splicing networks of cancer cells. Findings from these studies rationalize the design of small molecules that can block SRRM4 functions that make NECP vulnerable to existing anti-cancer therapies. In collaboration with Dr. Art Cherkasov, we are also designing new catalytic topoisomerase II inhibitors to target the AR signalling driven by AR splice variants and AR mutants.
What is the significance of the findings in this publication?
This study defines the molecular mechanism by which the RNA splicing factor SRRM4 modulates RNA splicing of the histone demethylase BHC80 to confer cancer cells growth advantages and promote NEPC progression. It links RNA splicing and epigenetic modification of histones that can trigger the immune responses of tumour cells to induce multiple tumour promoting cytokines. We found that the major downstream effector of SRRM4-BH80 axis involves MyD88 signalling, and showed proof-of-principle evidence that MyD88 inhibitors can suppress the growth of NEPC spheroids and xenografts. These studies provide insights on designing future therapeutic strategies to control NEPC development and progression. This is a collaborative work with several VPC PIs including Colin Collins, Martin Gleave, YZ Wang, Ladan Fazli and Dr. Jiaoti Huang Head of Department of Pathology Duke University and Dr. Catherine Musselman from University of Iowa.
What are the next steps for this research?
We believe the concept that alternative RNA splicing modulates the epigenome of cancer cells is critical for tumour cell plasticity. We therefore aim at globally profiling epigenome of prostate cancers regulated by SRRM4 to deepen our understanding of therapy-resistant prostate cancers. We hope to design SRRM4 inhibitors or small molecules of key enzymes that modulate the NEPC epigenome.
This work was funded by:
These works are supported by the CIHR, Prostate Cancer Canada, the Terry Fox Foundation of Cancer Research and NIH Prostate Cancer SPORE.
