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Published on: June 7, 2019
TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss
Karolina Pietrzak1,2, Rostyslav Kuzyakiv1,3, Ronald Simon4
1Department of Molecular Mechanisms of Disease, DMMD, University of Zürich, CH-8057 Zürich, Switzerland.
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.
Insights
This study introduces a novel mouse organoid model for prostate cancer (PCa) research. The model reveals TIP5
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) presents significant clinical and molecular heterogeneity, complicating research and treatment.
- Existing in vitro models do not fully capture PCa's complexity, including cell of origin and event sequencing.
- The tumor suppressor gene PTEN (phosphatase and tensin homolog) deletion is a key event in PCa development.
Purpose of the Study:
- To establish a novel in vitro mouse prostate cancer model using organoid technology.
- To investigate the role of the chromatin regulator TIP5 in PCa initiation, particularly in PTEN-deleted (PTEN-del) PCa.
- To identify a PTEN gene signature for stratifying aggressive PCa.
Main Methods:
- Development of a mouse organoid model mimicking PTEN deletion in prostate cancer.
- Analysis of TIP5 expression in relation to PTEN-del PCa and patient outcomes.
- Cross-species analysis to identify a PTEN gene signature associated with aggressive PCa.
Main Results:
- High TIP5 expression combined with PTEN-del PCa correlates with reduced PSA recurrence-free survival.
- TIP5 is crucial for initiating PTEN-loss-mediated PCa of luminal origin but not for established transformation.
- A PTEN gene signature identified aggressive PCas with PTEN-del, high TIP5, and a TIP5-regulated expression profile.
Conclusions:
- Organoid modeling is a powerful tool for studying genetic alterations in PCa in a time- and cell-of-origin-specific manner.
- TIP5 plays a critical, time-dependent role in PTEN-loss-driven prostate cancer initiation.
- The identified PTEN gene signature aids in stratifying aggressive PCa for improved clinical management.
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