UCLA

Cellular differentiation is a fundamental process in growth and multicellular development. Trans-differentiation from adenocarcinoma to small cell neuroendocrine carcinoma in lung and prostate cancers can occur de novo or induced by targeted therapies. To understand the evolving process of the trans-differentiation, a temporal multi-omics study on a forward transformation in vitro/in vivo model of small cell neuroendocrine prostate cancer was performed. By analyzing samples taken from various time points including human basal cells, in vitro transformed organoids, early, transitional, and late xenograft tumors, an arc-like transformation trajectory with bifurcated endpoints defined by ASCL1 and ASCL2 is identified. Concurrently, the transcriptional programs shift from stress-response to cellular reprogramming, to neuroendocrine differentiation. With further experimental testing, additional transcription factors such as TFAP4 exhibit dynamic control between ASCL1 and ASCL2 expression. This study provides comprehensive epigenetic landscape of trans-differentiation and potential therapeutic targets for advanced prostate cancer.