TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN -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 PTEN (PTEN-del) can be modeled through Pten-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 PTEN-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 Pten-loss whereas it is dispensable once Pten-loss mediated transformation is established. Cross-species analyses revealed a PTEN gene signature that identified a group of aggressive primary PCas characterized by PTEN-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.

BAZ2A association with H3K14ac is required for the transition of prostate cancer cells into a cancer stem-like state

“…Remarkably, treatment with BAZ2A-BRD inhibitors BAZ2-ICR or GSK2801 impaired Pten -loss mediated transformed phenotype as evident by the translucent phenotype, the intact bilayer structure, and low Ki67 signal displayed by the majority of organoids treated with BAZ2A-BRD inhibitors whereas EZH2 inhibitor GSK126 did not show any significant effect. These results are consistent with previous data showing that BAZ2A is required for the initiation of PCa driven by Pten -loss (Pietrzak et al, 2020) and highlighted an important role of BAZ2A-BRD in this process. Collectively, these data indicate that pharmacological targeting of BAZ2A-BRD abolish the transition of PCa cells into a CSC-like state and the oncogenic transformation mediated by Pten -loss.…”

“…4e ). Consistent with previous reports (Karthaus et al, 2014; Pietrzak et al, 2020), compared to control organoids, shRNA- Pten organoids displayed altered morphology as evident by the solid and compact structure and elevated expression of nuclear proliferation marker Ki67 ( Fig. 4f-h ).…”

“…PTEN was also shown to have a pivotal role in CSCs by regulating pathways critical for stem cell maintenance, homeostasis, self-renewal and migration (Luongo et al, 2019; Mulholland et al, 2009; Wang et al, 2006). Furthermore, recent results showed that BAZ2A is required for the initiation of PCa driven by PTEN -loss (Pietrzak et al, 2020). Downregulation of Pten was achieved by infection of prostate organoids with lentivirus encoding shRNA- Pten , which allowed 80% reduction of Pten levels ( Supplementary Fig.…”

“…Furthermore, high BAZ2A levels in tumors associate with poor prognosis and disease recurrence. Finally, it was shown that BAZ2A is required for the initiation of PCa driven by PTEN - loss, one of the most commonly lost tumor suppressor gene in PCa (Pietrzak et al, 2020).…”

Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states

“…Treating prostate cancer with immune checkpoint inhibition has had limited efficacy to date and these therapies have largely focused on advanced castrationresistant tumors 43,44,[86][87][88][89][90] 68,93,94 . This might be due to a limitation of detection using single cell sequencing technology or that we could not robustly grow differentiated luminal cells 73 .…”