Dataset Information

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.

SUBMITTER: Pietrzak K

PROVIDER: S-EPMC7035629 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Pietrzak Karolina K Kuzyakiv Rostyslav R Simon Ronald R Bolis Marco M Bär Dominik D Aprigliano Rossana R Theurillat Jean-Philippe JP Sauter Guido G Santoro Raffaella R

Proceedings of the National Academy of Sciences of the United States of America 20200205 7

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 mou ...[more]

PMID: 32024754

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Project description:The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.

Dataset Information

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

Publications

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

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