The Transcriptomic Heterogeneity in Prostate Cancer

Prostate cancer affects millions of people worldwide. The current risk stratification and disease management strategies are not sufficient. Understanding the molecular basis of prostate cancer can help address these clinical needs. While the genome is extensively investigated, the transcriptome of prostate cancer is much less well characterized. I have worked to unravel the transcriptomic heterogeneity in prostate cancer. I investigated the transcriptome of primary tumors with ultra-deep total RNA-seq and identified widespread RNA circularization in prostate cancer for the first time: the average tumor expressed 7,232 distinct circular transcripts and circRNAs showed a highly tissue specific expression pattern. The parental genes of circRNAs showed distinct characteristics and the circular transcriptome harbors unique prognostic information. The degree of circRNA production is directly correlated to disease progression in multiple patient cohorts. Loss of function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ~90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth partially through regulating microRNA miR-181. In two side projects, I interrogated the tumor transcriptome from two different aspects: First, I tackled the intra-tumoral heterogeneity at single cell resolution and identified multiple transcriptomic reprogramming associated with tumor progression in primary tumors (Appendix I). Second, I worked to outline the transcriptional regulatory mechanism of the histone demethylation protein LSD1 on the pioneer transcription factor FOXA1 in prostate cancer (Appendix II). Together, my work reiterated the importance of transcriptomic study in prostate cancer: it provided novel insights into prostate cancer biology, offered multiple opportunities for future investigation and pinpointed actionable targets for advanced tumors.Ph.D