Androgen receptor cell-autonomously regulates luminal cell plasticity [ATAC-Seq]
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ABSTRACT:
PROVIDER: PRJNA1311816 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Androgen receptor cell-autonomously regulates luminal cell plasticity [RNA-Seq]
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Project description:ATAC-seq was performed using intact, Ar knockout or castrated luminal cell after 2 weeks Ar knockout or 5 days castration
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Project description:Cells in the prostate are postulated to have stem cell properties based on organ regeneration following castration. Through single cell RNA-seq (scRNA-Seq) analysis, we identify a rare luminal cell population in the mouse prostate that expresses stem-like markers (Sca1+, Psca+), as well as a larger population of more differentiated cells (Nkx3.1+, Pbsn+, CD133/Prom1+). Unexpectedly, both populations acquire enhanced organoid regeneration potential following castration and contribute equipotently to prostatic regeneration, as revealed by lineage tracing. Regeneration is mediated, in part, by androgen-driven expression of Nrg2, Igf1, Fgf10 and Rspo3 by distinct populations of mesenchymal cells acting in a paracrine fashion on luminal cells. Human prostate tissue contains similar differentiated and stem-like luminal subpopulations which also, collectively. acquire enhanced regenerative potential after androgen ablation therapy. Thus, nearly all luminal cells that persist post-castration contribute to prostate regeneration, not just rare stem cells.
2020-05-01 | GSE146811 | GEO
Project description:FOXA1 is recurrently altered in hormone-driven malignancies, with activating hotspot mutations detected in 10-40% of primary prostate cancers based on ethnicity. Yet, the tumorigenic potential and pathobiology of FOXA1 remain unexplored in vivo. Here, we generated and characterized knock-in mouse models harboring FOXA1 mutant transgenes that represent distinct classes of activating mutations. Our findings reveal that FOXA1 class 1 mutations (i.e., wing 2 alterations) in a Trp53-null background, drive high-grade, invasive luminal adenocarcinoma with full penetrance by 40 weeks of age. These hyperproliferative lesions retain luminal characteristics, gain expression of NSD2, and regress upon androgen withdrawal—mirroring features of primary human prostate adenocarcinomas. Mechanistically, class 1 mutants aberrantly activate mTORC1/2 signaling and reprogram androgen receptor (AR) activity by expanding the enhancer landscape at non-canonical chimeric AR-half elements enriched in patient tumors. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) do not drive transformation but induce intra-luminal plasticity in androgen-intact normal tissues, which is otherwise triggered in response to castration. Class 2 mutants lead to a 10- to 20-fold expansion of Ar+/Ck8+ luminal epithelia expressing stem/progenitor markers such as Trop2, Ck4, and Psca. Mechanistically, class 2 mutants maintain AR activity while de-compacting over 40,000 new cis-regulatory elements bound by Klf5 and AP-1 transcription factors to activate stemness and WNT gene programs. Class 2-mutant-expressing prostate epithelial cells resist castration-induced atrophy, remain proliferative in androgen-deprived conditions, and form organoids and allografts at higher frequencies. Additionally, metastatic prostate tumors from patients harboring class 2 mutations show elevated KLF5 expression and stemness signatures. Collectively, our data establish FOXA1 as a critical oncogene in both primary and advanced AR-dependent prostate cancers, revealing its functional versatility in driving either tumor initiation or therapy resistance depending on the mutation class.
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Project description:Luminal Androgen Receptor-Enriched tripple Negative Breast Cancer
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Project description:FOXA1 is recurrently altered in hormone-driven malignancies, with activating hotspot mutations detected in 10-40% of primary prostate cancers based on ethnicity. Yet, the tumorigenic potential and pathobiology of FOXA1 remain unexplored in vivo. Here, we generated and characterized knock-in mouse models harboring FOXA1 mutant transgenes that represent distinct classes of activating mutations. Our findings reveal that FOXA1 class 1 mutations (i.e., wing 2 alterations) in a Trp53-null background, drive high-grade, invasive luminal adenocarcinoma with full penetrance by 40 weeks of age. These hyperproliferative lesions retain luminal characteristics, gain expression of NSD2, and regress upon androgen withdrawal—mirroring features of primary human prostate adenocarcinomas. Mechanistically, class 1 mutants aberrantly activate mTORC1/2 signaling and reprogram androgen receptor (AR) activity by expanding the enhancer landscape at non-canonical chimeric AR-half elements enriched in patient tumors. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) do not drive transformation but induce intra-luminal plasticity in androgen-intact normal tissues, which is otherwise triggered in response to castration. Class 2 mutants lead to a 10- to 20-fold expansion of Ar+/Ck8+ luminal epithelia expressing stem/progenitor markers such as Trop2, Ck4, and Psca. Mechanistically, class 2 mutants maintain AR activity while de-compacting over 40,000 new cis-regulatory elements bound by Klf5 and AP-1 transcription factors to activate stemness and WNT gene programs. Class 2-mutant-expressing prostate epithelial cells resist castration-induced atrophy, remain proliferative in androgen-deprived conditions, and form organoids and allografts at higher frequencies. Additionally, metastatic prostate tumors from patients harboring class 2 mutations show elevated KLF5 expression and stemness signatures. Collectively, our data establish FOXA1 as a critical oncogene in both primary and advanced AR-dependent prostate cancers, revealing its functional versatility in driving either tumor initiation or therapy resistance depending on the mutation class.
2025-07-02 | GSE280835 | GEO
Project description:FOXA1 is recurrently altered in hormone-driven malignancies, with activating hotspot mutations detected in 10-40% of primary prostate cancers based on ethnicity. Yet, the tumorigenic potential and pathobiology of FOXA1 remain unexplored in vivo. Here, we generated and characterized knock-in mouse models harboring FOXA1 mutant transgenes that represent distinct classes of activating mutations. Our findings reveal that FOXA1 class 1 mutations (i.e., wing 2 alterations) in a Trp53-null background, drive high-grade, invasive luminal adenocarcinoma with full penetrance by 40 weeks of age. These hyperproliferative lesions retain luminal characteristics, gain expression of NSD2, and regress upon androgen withdrawal—mirroring features of primary human prostate adenocarcinomas. Mechanistically, class 1 mutants aberrantly activate mTORC1/2 signaling and reprogram androgen receptor (AR) activity by expanding the enhancer landscape at non-canonical chimeric AR-half elements enriched in patient tumors. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) do not drive transformation but induce intra-luminal plasticity in androgen-intact normal tissues, which is otherwise triggered in response to castration. Class 2 mutants lead to a 10- to 20-fold expansion of Ar+/Ck8+ luminal epithelia expressing stem/progenitor markers such as Trop2, Ck4, and Psca. Mechanistically, class 2 mutants maintain AR activity while de-compacting over 40,000 new cis-regulatory elements bound by Klf5 and AP-1 transcription factors to activate stemness and WNT gene programs. Class 2-mutant-expressing prostate epithelial cells resist castration-induced atrophy, remain proliferative in androgen-deprived conditions, and form organoids and allografts at higher frequencies. Additionally, metastatic prostate tumors from patients harboring class 2 mutations show elevated KLF5 expression and stemness signatures. Collectively, our data establish FOXA1 as a critical oncogene in both primary and advanced AR-dependent prostate cancers, revealing its functional versatility in driving either tumor initiation or therapy resistance depending on the mutation class.
2025-07-02 | GSE280834 | GEO
Project description:FOXA1 is recurrently altered in hormone-driven malignancies, with activating hotspot mutations detected in 10-40% of primary prostate cancers based on ethnicity. Yet, the tumorigenic potential and pathobiology of FOXA1 remain unexplored in vivo. Here, we generated and characterized knock-in mouse models harboring FOXA1 mutant transgenes that represent distinct classes of activating mutations. Our findings reveal that FOXA1 class 1 mutations (i.e., wing 2 alterations) in a Trp53-null background, drive high-grade, invasive luminal adenocarcinoma with full penetrance by 40 weeks of age. These hyperproliferative lesions retain luminal characteristics, gain expression of NSD2, and regress upon androgen withdrawal—mirroring features of primary human prostate adenocarcinomas. Mechanistically, class 1 mutants aberrantly activate mTORC1/2 signaling and reprogram androgen receptor (AR) activity by expanding the enhancer landscape at non-canonical chimeric AR-half elements enriched in patient tumors. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) do not drive transformation but induce intra-luminal plasticity in androgen-intact normal tissues, which is otherwise triggered in response to castration. Class 2 mutants lead to a 10- to 20-fold expansion of Ar+/Ck8+ luminal epithelia expressing stem/progenitor markers such as Trop2, Ck4, and Psca. Mechanistically, class 2 mutants maintain AR activity while de-compacting over 40,000 new cis-regulatory elements bound by Klf5 and AP-1 transcription factors to activate stemness and WNT gene programs. Class 2-mutant-expressing prostate epithelial cells resist castration-induced atrophy, remain proliferative in androgen-deprived conditions, and form organoids and allografts at higher frequencies. Additionally, metastatic prostate tumors from patients harboring class 2 mutations show elevated KLF5 expression and stemness signatures. Collectively, our data establish FOXA1 as a critical oncogene in both primary and advanced AR-dependent prostate cancers, revealing its functional versatility in driving either tumor initiation or therapy resistance depending on the mutation class.
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