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Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [ChIP-Seq]

ABSTRACT: Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.

ORGANISM(S): Mus musculus

PROVIDER: GSE164968 | GEO | 2022/07/14

REPOSITORIES: GEO

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Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [scRNA-Seq 2]

Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.

2022-07-14 | GSE164970 | GEO

Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [scRNA-Seq 1]

2022-07-14 | GSE164969 | GEO

Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [RNA-Seq]

2022-07-14 | GSE164967 | GEO

Elucidating the mechanism underlying prostate turmorigenesis mediated by AR in Shh-responsive cells

Project description:The activation of the androgen receptor (AR) through binding of androgens is essential for prostate tumorigenesis. Although significant effort has been devoted to determining the intrinsic mechanism underlying AR action and designing therapies to directly target AR expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using both in vivo tissue recombination assays and mouse models. Single-cell RNA sequencing combined with other experimental analyses showed that AR loss in stromal Gli1-lineage niches resulted in robust increased expression of insulin-like growth factor binding protein 3 (IGFBP3) through attenuation of AR suppression on Sp1-regulated transcription. Aberrant increased IGFBP3 further inhibits IGF1 induced Wnt signaling activation in subsets of basal epithelial cells, impairing oncogenic cell growth and tumor development. IGFBP3 further showed to attenuate IGF1-induced oncogenic growth of prostatic organoids derived from mouse basal epithelia. Loss of human prostate tumor basal cell signatures was identified in basal cells with AR-deficient microenvironment. This study demonstrates the niche effect of stromal AR in Gli1-lineage cells in supporting prostate tumorigenesis, implicating co-targeting tumor epithelial and stromal AR signaling for treating advanced prostate cancer.

2022-10-07 | GSE174471 | GEO

Gene expression profiles (stroma and epithelium) of prostate cancer mouse models (JOCK1, Pro-Cat M-CM-^W JOCK1, Ubi-Cat M-CM-^W JOCK1)

Project description:The fibroblast growth factor receptor (FGFR) and canonical Wnt signaling pathways are important regulators of carcinogenesis; however, the interaction between these two pathways in the context of prostate cancer (PCa) has not been fully elucidated. Using novel transgenic mouse models, we describe Wnt-induced synergistic acceleration of FGFR1-driven adenocarcinoma; largely due to pronounced fibroblastic reactive stroma (RS) activation surrounding prostatic intraepithelial neoplasia (PIN) lesions in endogenous and reconstitution assays. Finally, both mouse and human RS are characterized by increases in TGF-M-NM-2 signaling heterogeneity immediately adjacent to PIN lesions; however, heterogeneity is lost during later stages of progression, likely contributing to tissue invasion. These studies confirm the importance of the FGFR1-Wnt-TGF-M-NM-2 signaling axes as driving forces behind reactive stroma and aggressive adenocarcinoma. To elucidate the mechanism behind the Wnt-accelerated FGFR1 adenocarcinoma, we performed laser capture microdissection (LCM) to separate pre-cancerous (hyperplasia and PIN) epithelia and adjacent reactive-stroma cells. We utilized frozen samples from specific time points (JOCK1, 40 weeks, Pro-Cat M-CM-^W JOCK1 and Ubi-Cat M-CM-^W JOCK1, 24 weeks) and performed gene expression profiling on the respective tissues.

2014-01-07 | E-GEOD-41344 | biostudies-arrayexpress

Gene expression profiles (stroma and epithelium) of prostate cancer mouse models (JOCK1, Pro-Cat × JOCK1, Ubi-Cat × JOCK1)

2014-01-07 | GSE41344 | GEO

Stromal androgen and hedgehog signaling regulates stem cell niches in pubertal prostate development

Project description:Androgen-signaling is essential for prostate development. However, how androgen action facilitates prostatic stem/progenitor initiated pubertal prostatic growth remains unclear. Here, we demonstrate that androgens regulate Shh-signaling to control the cellular niche in prostatic epithelial development. Selective deletion of androgen receptor (AR) in stromal Shh-responsive cells significantly impedes pubertal prostatic epithelial morphogenesis and growth. Dysregulation of developmental signaling networks revealed in both prostatic stromal and epithelial cells of AR-deficient mice. Specifically, deletion of AR yielded increased Gli1 expression in prostatic stromal cells, elevated Shh expression in adjacent epithelial cells and stark inhibition of prostate cell growth. Trajectory analysis revealed AR deletion induces abnormal differentiation patterns of prostatic epithelia. Recombination of prostatic epithelial cells with AR-deficient stromal Gli1-expressing cells fails to develop normal prostatic epithelia. These data demonstrate the decisive role of stromal AR in interacting with Shh-signaling in the cellular niche to control pubertal prostatic morphogenesis and growth.

2021-08-27 | GSE156168 | GEO

SPOP mutation - SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Project description:Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.

2017-03-20 | PXD005309 | Pride

LOSS OF THE TUMOR SUPPRESSOR, TP53, ENHANCES THE ANDROGEN RECEPTOR MEDIATED ONCOGENIC TRANSFORMATION AND TUMOR DEVELOPMENT IN THE MOUSE PROSTATE

Project description:Androgen signaling is essential for prostate tumorigenesis. The tumor suppressor p53 has been implicated in prostate cancer progression. Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 deletion are frequently altered in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess these genetic abnormalities in the prostate. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic what happens in human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors. Histological analysis showed pathological lesions resembling prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses showed a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. The Master Regulator Analysis further identified SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a co-regulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. These results demonstrate a novel mechanism underlying elevated AR expression and Trp53 deletion induced prostate cancer cell trans-differentiation, aggressiveness, and progression.

2019-04-03 | GSE129243 | GEO

Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Project description:Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of prostatic precancerous lesions to malignant tumors provides a broad time-frame for strategies targeting disease emergence. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on prostates of genetically-engineered Pten(i)pe- /- mice. We discovered that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells during disease progression. Luminal HIF1A enhances glucose metabolism and promotes a PIN-derived secretome that increases the recruitment of myeloid-derived suppressor cells, thus dampening immune surveillance. Moreover, pharmacological inhibition of HIF1A induces apoptosis in early PIN lesions, and slows the proliferation of late ones. Therefore, our study identifies HIF1A as a target for PCa prevention. Importantly, we also demonstrate that HIF1A signaling correlates with the emergence of prostatic luminal cells expressing TGM2, the expression of which predicts early relapse after primary intervention in PCa patients.

2022-06-07 | GSE186419 | GEO

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