Towards understanding the role of the minor spliceosome in prostate cancer (Dr. Anke Augspach, Postdoc)
Alternative splicing, a process by which a single message (referred to as RNA) can give rise to several different proteins represents a non-genetic variability known to play a major role in cancer development and progression, yet the precise molecular mechanisms by which the various splice variants are generated remain unclear. Splicing is carried out by two large and complex molecular machines. While the major mechanism, responsible for more than 99% of all splicing, is well characterized, the minor mechanism is poorly understood. In this project, we aim to further understand the role of the minor spliceosome in (prostate) cancer development and resistance to pave the way for new therapeutic and diagnostic tools for high-risk/advanced (prostate) cancer patients.
We currently have our first study in late revision stage at Cell. In this first study, we explored the role of minor spliceosome (MiS) and minor intron-containing gene (MIG) expression in prostate cancer (PCa). We show MIGs are enriched as direct interactors of cancer-causing genes and their expression discriminates PCa progression. Increased expression of U6atac MiS snRNA, including others, and 6x more efficient minor intron splicing was observed in castration-resistant PCa (CRPC) versus primary PCa. Notably, androgen receptor signaling influenced MiS activity. Inhibition of MiS through siU6atac in PCa caused minor intron mis-splicing and aberrant expression of MIG transcripts and encoded proteins, which enriched for MAPK activity, DNA repair and cell cycle. Single cell-RNAseq confirmed cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. siU6atac was ~50% more efficient in lowering tumor burden of CRPC cells and organoids versus current state-of-the-art combination therapy. In all, MiS is a strong therapeutic target for lethal PCa and potentially other cancers. Based on these observations, the University of Bern has filed a patent application in the area of diagnostics and therapeutics and we are in the process of starting a company around a minor spliceome platform for cancer and viral therapy.
This project has been funded by a Fond’action contre le cancer young investigator award and Prostate Cancer Foundation Challenge Award.
Figure. U6atac expression, MiS activity, and minor intron splicing correlate with PCa therapy resistance and PCa progression to CRPC-adeno and transdifferentiation to CRPC-NE. One major MiS regulator during that process is the AR-axis, which is re-activated during CRPC-adeno and blocked in CRPC-NE. Molecularly, an increase in MiS dependent splicing promotes changes of transcriptome and proteome. This results in cell cycle activation, increased MAPK signalling and increased DNA repair. U6atac mediated MiS inhibition renders MiS splicing error-prone through increased intron retention and alternative splicing events, which results in cell cycle block and decreased MAPK signalling and DNA repair. MiS inhibition blocks all stages of PCa. Figure created with BioRender.com