Targeted reprogramming of aggressive prostate cancers towards a benign transcriptional state
Master transcription factors regulate normal cellular identity through control of essential gene-signaling networks and are often dysregulated during tumorigenesis and growth. Here we apply a reprogramming algorithm to identify the master regulators operating in normal prostate cells, as well as master regulators operating in a cohort of aggressive and therapy-resistant human prostate cancers. We validated the role of cancer- or benign-associated master regulators using matching organoids derived from human prostate cancer xenografts.
Knockdown of master regulators predicted for aggressive prostate cancers revealed multiple tumour cell dependencies, with significant growth inhibition of both adenocarcinoma and neuroendocrine prostate cancer types. Additionally, overexpression of benign master regulators in aggressive cancer cells forced their reprogramming towards a less aggressive cellular state. Therapeutic compounds were prioritized based on their ability to target key master regulator networks and validated experimentally.
Our approach presents a novel avenue to identify master regulators operating in aggressive prostate cancers with diverse mutational backgrounds. Furthermore, we demonstrate the ability to reprogram prostate cancer cells towards a benign transcriptional and functional state.