Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (Bulk RNA-Seq)

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells. To study the temporal transcriptional landscape during this trans-differentiation process, we conducted a time course study using a PARCB model by integrating multi-omics sequencing, including bulk RNA-sequencing and ATAC-sequencing on samples taken at different time point, as well as single cell RNA sequencing on serial xenograft tumors. ------------------------------------- Authors state: Raw data was not uploaded to GEO/not included in metadata as they are deposited in dbGaP with accession number phs003230.v1.p1