RUNX1T1 drives stem-like small-cell neuroendocrine prostate cancer identity

Neuroendocrine prostate cancer (NEPC) or small-cell neuroendocrine prostate cancer (SCNPC) is increasingly recognized as a treatment-resistant disease arising among prostate adenocarcinoma (PRAD) patients. It has no effective therapy due to incomplete understanding of the mechanisms underlying treatment-induced cancer cell identity switching. Here, we identified RUNX1 Partner Transcriptional Co-Repressor 1 (RUNX1T1) as a frequently amplified gene in prostate cancer patients, associated with a poorer prognosis. RUNX1T1 is highly expressed and progression-correlated in NEPC and SCNPC. We found that RUNX1T1 is essential for SCNPC survival, as its knockdown induced apoptotic cell death and the acquisition of PRAD-like identity, including alterations in genes involved in cell-cell adhesion and epithelial cell polarity. Functional assays in prostate cancer cell lines revealed that RUNX1T1 regulates genes associated with stemness and the maintenance of neuroendocrine identity in SCNPC. Using our human cell reprogramming assay, which mimics the development of PRAD or SCNPC in vivo, we further demonstrated that RUNX1T1 is required to initiate neuroendocrine differentiation (NED), histological feature changes, and stemness. Its knockout abolished expression of NED and stemness markers and induced loss of SCNPC histological features during SCNPC development. Collectively, these findings establish RUNX1T1 as a critical driver of the cell identity of stem-like SCNPC. Understanding the mechanisms by which RUNX1T1 exerts its versatile regulation of proliferation, stemness, and SCNPC differentiation will in turn pave the way for the discovery of new, specific therapeutic targets to prevent SCNPC progression.