A forward genetic screen identifies Sirtuin1 as a driver of neuroendocrine prostate cancer

To identify drivers of aggressive prostate cancer, we conducted a Sleeping Beauty (SB) transposon mutagenesis screen based on a mouse model having conditional loss of function of Pten and Tp53 prostate (NPp53). Compared with the control mice (NPp53-SB(—)), the experimental mice (NPp53-SB(+)) develop aggressive prostate cancer phenotypes that are highly heterogeneous and highly metastasis.

Most notably, a high percentage of NPp53-SB(+) prostate tumors have features of NEPC, which are conserved with human prostate cancer. To identify and prioritize drivers of NEPC in these NPp53-SB(+) tumors, we used a novel integrative approach that combines (i) genomic analyses of common insert sites (CIS) for the SB transposon, (ii) VIPER analyses of control NPp53-SB(+) prostate tumors to identify master regulators (MRs) enriched in NEPC, and (iii) comparative transcriptomic analyses with data from human prostate cancer patients followed by integrative analyses using of these data using a CINDy algorithm to identify CIS-associated genes that modulate the NEPC phenotypes.