Androgen receptor mediated gene regulatory networks in prostate cancer

To enhance this approach, a conventional peak calling and a novel machine learning approach, LanceOtron was employed, to identify binding sites that would otherwise be missed by applying rigid thresholding to peak calling. Chromatin immunoprecipitation (ChIP), is used to map AR recruitment to the genome, which conventionally has sensitivity issues and creates challenges when working with low cell numbers/heterogenous samples.

To address this, I have used a “low cell ChIP” method known as MNase ChIP for the first time to assess AR recruitment to chromatin.Finally, to provide insights into the transcriptional impact of stromal and immune cells on PCa cells, a pre-clinical co-culture model was used. Using a combination of phenotypic assays, ChIP, transcript profiling and metabolomics I show that co-culture with either stromal or immune cells induces HIF1α signaling and TGF beta responses, leading to a more glycolytic state with partial EMT in cells and reduced recruitment of AR to many canonical ARBs.

This recapitulates some of the key changes that occur in tissue during the emergence of treatment resistance disease and provides a framework for future translational studies to further address the crosstalk between this signaling and changes in AR activity.<br><br>