The Sca-1+ and Sca-1− mouse prostatic luminal cell lineages are independently sustained

Kwon, Oh-Joon; Choi, Jong Min; Zhang, Li; Jia, Dongyu; Li, Zhouyihan; Zhang, Yiqun; Jung, Sung Yun; Creighton, Chad J.; Li, Xin

doi:10.1002/stem.3253

Cited by 16 publications

(26 citation statements)

References 52 publications

(80 reference statements)

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“…Previously, we discovered a distinct Sca-1 + Nkx3.1 − luminal cell population that resides in the mouse proximal prostatic duct adjacent to the urethra ( 16 , 17 ). These cells express Sox2, are replicative quiescent, and possess a facultative bipotent differentiation capacity ( 16 – 20 ).…”

Section: Resultsmentioning

confidence: 99%

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Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

et al. 2020

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Prostate adenocarcinoma undergoes neuroendocrine differentiation to acquire resistance toward anti-hormonal therapies. The underlying mechanisms have been investigated extensively, among which Sox2 has been shown to play a critical role. However, genetic evidence in mouse models for prostate cancer to support the crucial role of Sox2 is missing. The adult mouse prostate luminal cells contain both castration-resistant Sox2-expressing Sca-1 + cells and castration-responsive Sca-1 − cells. We show that both types of the luminal cell are susceptible to oncogenic transformation induced by loss of function of the tumor suppressor Pten . The tumors derived from the Sca-1 + cells are predisposed to castration resistance and castration-induced neuroendocrine differentiation. Genetic ablation of Sox2 suppresses neuroendocrine differentiation but does not impact the castration resistant property. This study provides direct genetic evidence that Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation of Pten null prostate adenocarcinoma, corroborates that the lineage status of the prostate cancer cells is a determinant for its propensity to exhibit lineage plasticity, and supports that the intrinsic features of cell-of-origin for prostate cancers can dictate their clinical behaviors.

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Section: Resultsmentioning

confidence: 99%

“…The Sca-1 + luminal cells do not rely on androgen for their survival ( 17 , 18 , 20 ). To examine whether tumors derived from the Sca-1 + luminal cells inherit the castration resistant property of their cells of origin, we castrated K8-Pten mice at 3 months after tamoxifen induction ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

et al. 2020

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“…The human TACSTD2 high luminal cells share molecular features with the castration resistant Sca-1 + luminal cells in mice ( 28 ). To determine the androgen dependency of the tumor organoids, we passaged and cultured organoid cells without testosterone but with enzalutamide.…”

Section: Resultsmentioning

confidence: 99%

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc

et al. 2020

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Summary Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2 high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2 high and TACSTD2 low luminal cells transduced by activated AKT and c-Myc can form organoids containing versatile clinically relevant tumor cell lineages with regard to the expression of AR and the neuroendocrine cell markers Synaptophysin and Chromogranin A. Tumor organoid cells derived from the TACSTD2 high luminal cells are more predisposed to neuroendocrine differentiation along passaging and are relatively more castration-resistant. Knocking down TACSTD2 and SOX2 both attenuate neuroendocrine differentiation of tumor organoid cells. This study demonstrates de novo neuroendocrine differentiation of the human prostate luminal epithelial cells induced by caAKT and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.

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“…Initially, we set out to assess whether mouse prostate organoids are a representative and informative model for the study of the prostate epithelium, in light of recent discoveries on prostate cellular heterogeneity and dynamics 27,28,[30][31][32]34,38 . Considering our interest in signalling, we focused on a culture method in defined media conditions.…”

Section: Mouse Prostate Organoid Cultures Enable the Continuous Expanmentioning

confidence: 99%

“…Recent single-cell studies have confirmed the enrichment of a variety of epithelial progenitors -basal, luminal proximal (LumP), and periurethral (PrU) cells -in this anatomical district, though also present at low frequency in the distal compartment [27][28][29][30][31][32] . Such cells are known to be particularly quiescent during homeostasis 33,34 , but also to exhibit extensive regenerative potential in ex-vivo assays 31,35 .…”

Section: Introductionmentioning

confidence: 99%

Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

Cambuli

Foletto

Alaimo

et al. 2021

Preprint

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The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during ageing, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce cytostasis in a large variety of epithelia, but the intracellular pathway mediating this signal in the prostate, as well as its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we found that intra-epithelial non-canonical Activin A signalling inhibited cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggered Tak1 and p38 ΜAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurred upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro were also able to implant with increased frequency into immunocompetent mice. Our study demonstrates that non-canonical Activin A signalling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumour progenitors.

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The Sca-1+ and Sca-1− mouse prostatic luminal cell lineages are independently sustained

Cited by 16 publications

References 52 publications

Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

Sox2 is necessary for androgen ablation-induced neuroendocrine differentiation from Pten null Sca-1+ prostate luminal cells

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc

Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

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