TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss

TY - JOUR

T1 - TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss

AU - Pietrzak, Karolina

AU - Kuzyakiv, Rostyslav

AU - Simon, Ronald

AU - Bolis, Marco

AU - Bär, Dominik

AU - Aprigliano, Rossana

AU - Theurillat, Jean-Philippe

AU - Sauter, Guido

AU - Santoro, Raffaella

N1 - Copyright © 2020 the Author(s). Published by PNAS.

PY - 2020/2/18

Y1 - 2020/2/18

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinogenesis

KW - Cell Transformation, Neoplastic

KW - Chromosomal Proteins, Non-Histone/genetics

KW - Gene Deletion

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Male

KW - Mice

KW - Mice, Knockout

KW - PTEN Phosphohydrolase/genetics

KW - Prostate/metabolism

KW - Prostatic Neoplasms/genetics

U2 - 10.1073/pnas.1911673117

DO - 10.1073/pnas.1911673117

M3 - SCORING: Journal article

C2 - 32024754

VL - 117

SP - 3637

EP - 3647

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 7

ER -