TIP5 primes prostate luminal cells for the oncogenic transformation mediated by <i>PTEN</i>-loss.

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men. Its clinical and molecular heterogeneities and the lack of in vitro models outline the complexity of PCa in the clinical and research settings. We established an in vitro mouse PCa model based on organoid technology that takes into account the cell of origin and the order of events. Primary PCa with deletion of the tumor suppressor gene <i>PTEN</i> (<i>PTEN</i>-del) can be modeled through <i>Pten-</i>down-regulation in mouse organoids. We used this system to elucidate the contribution of TIP5 in PCa initiation, a chromatin regulator that is implicated in aggressive PCa. High TIP5 expression correlates with primary <i>PTEN</i>-del PCa and this combination strongly associates with reduced prostate-specific antigen (PSA) recurrence-free survival. TIP5 is critical for the initiation of PCa of luminal origin mediated by <i>Pten</i>-loss whereas it is dispensable once <i>Pten</i>-loss mediated transformation is established. Cross-species analyses revealed a <i>PTEN</i> gene signature that identified a group of aggressive primary PCas characterized by <i>PTEN</i>-del, high-TIP5 expression, and a TIP5-regulated gene expression profile. The results highlight the modeling of PCa with organoids as a powerful tool to elucidate the role of genetic alterations found in recent studies in their time orders and cells of origin, thereby providing further optimization for tumor stratification to improve the clinical management of PCa.