Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation.

Trans -differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans -differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are 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, as well as connections to normal neuroendocrine cell states. [Display omitted] • PARCB temporal model profiling informs key aspects of SCNPC trans -differentiation • Trans -differentiation trajectory resembles a common developmental arc-like pattern • ASCL1 and ASCL2 mark distinct bifurcating SCNPC trans -differentiation trajectories • TFAP4 as a common regulator of ASCL1/2 implicated in SCNPC trans -differentiation Chen et al. use temporal profiling of a small cell neuroendocrine prostate cancer model to inform anti-androgen therapy-induced trans -differentiation. An arc-like trajectory common to developmental biology is observed, and a bifurcation marked by ASCL1 and ASCL2, with parallels to SCLC. TFAP4 is identified as a common regulator of ASCL1 and ASCL2. [ABSTRACT FROM AUTHOR]