Molecular Features of Aggressive Preinvasive Lesions driven by Combined MYC Activation and PTEN Loss in Mouse Prostate
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287166 | GEO | 2025/10/13
REPOSITORIES: GEO
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Project description:We used microarrays to analyze the global gene expression and identified differentially expressed gene list between wild-type anterior prostates and Pb-Cre4;PtenLoxP/LoxP anterior prostates, Pb-Cre4;PtenLoxP/LoxP;LrfLoxP/LoxP anterior prostates at 12 weeks of age. Prostate-specific Pten deletion (Pb-Cre4;PtenLoxP/LoxP) results in prostate intraepithelial neoplasia (PIN) which, following a long latency, can progress to high-grade adenocarcinoma, albeit with minimally invasive and metastatic features. However, inactivation of Lrf in the prostate epithelium in combination of Pten results in aggressive prostate tumors. To understand the molecular mechanisms by which loss of Lrf promotes Pten-loss-driven prostate tumorigenesis, we conducted transcriptome comparison of three wild-type anterior prostates, three Pb-Cre4;PtenLoxP/LoxP PIN, and three Pb-Cre4;PtenLoxP/LoxP;LrfLoxP/LoxP anterior prostate tumors.
2013-05-19 | E-GEOD-46473 | biostudies-arrayexpress
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
Project description:We used microarrays to detail the global gene expression and identified differentially expressed gene list between wild-type anterior prostates and Ptenpc-/- anterior prostates, Ptenpc-/-Smad4pc-/- and Ptenpc-/- anterior prostates, Ptenpc-/-p53pc-/- and Ptenpc-/- anterior prostates at 15 weeks of age. Prostate-specific Pten deletion (Ptenpc-/-) results in prostate intraepithelial neoplasia (PIN) which, following a long latency, can progress to high-grade adenocarcinoma, albeit with minimally invasive and metastatic features. To understand this feeble progression phenotype, we conducted transcriptome comparison of five Ptenpc-/- PIN relative to three wild-type anterior prostate. Moreover, Ptenpc-/-Smad4pc-/- progress to metastasis, while Ptenpc-/-p53pc-/- not progress to metastasis. To understand this phenotype difference, we conducted transcriptome comparison of five Ptenpc-/-Smad4pc-/-to five Ptenpc-/- prostate tumor, and three Ptenpc-/-p53pc-/- to five Ptenpc-/- tumor.
2010-11-05 | E-GEOD-25140 | biostudies-arrayexpress
Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression. Genotyped male mice were euthanized at 12 months of age and prostates isolated. Prostates were fixed overnight in 10% formalin and stored in 70% ethanol until tissue processing and paraffin embedding. Serial sections were cut from paraffin blocks which were stained for H&E and analyzed by a trained rodent histopathologist. Using these sections as a visual guide for specific types of lesions, the sequential sections were stained with hematoxylin and used for laser capture microdissection on ArcturusXT system. Epithelial cells within notable high grade prostate intraepithelial neoplasia (HG-PIN) lesions were microdissected from 3 mice from each corresponding genotype. In addition, poorly differentiated adenocarcinomas from PbCre;T-3Mb-Erg/+;PtenL/L mice were also dissected. RNA was isolated from the microdissected tissue using the Qiagen RNeasy FFPE kit and subjected to Nugen Amplification before microarray analysis on an Affymetrix Mouse Gene 2.0 ST chip.
2015-12-31 | E-GEOD-63070 | biostudies-arrayexpress
Project description:We performed expression mouse profiling of prostates of 3 month WT, ERG, PTEN f/f and Pten f/f;ERG mice. For WT and ERG prostates, entire prostates were dissected and total RNA immediated harvested. For Pten f/f and Pten f/f;ERG prostates, the Ventral Lobe was dissected.
2013-05-10 | GSE46799 | GEO
Project description:We performed expression mouse profiling of prostates of 3 month WT, ERG, PTEN f/f and Pten f/f;ERG mice. For WT and ERG prostates, entire prostates were dissected and total RNA immediated harvested. For Pten f/f and Pten f/f;ERG prostates, the Ventral Lobe was dissected. Mice are in the C57B6 background. The prostate were harvested and RNA isolated by standard protocols and analyzed by expression profiling.
2013-05-10 | E-GEOD-46799 | biostudies-arrayexpress
Project description:PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model we previously generated. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penitence. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, these data indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective in preventing the development of metastatic prostate cancers. Murine mutants with prostate specific loss of Pten and K-ras activation (K-rasG12D) under regulation of the probasin promoter developed high grade, invasive prostate cancer. RNA was extracted from dissected prostate lobes from individual mutants with pathology thought to closely mimic human disease. Prostate tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.
2012-02-28 | E-GEOD-34839 | biostudies-arrayexpress
Project description:PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model we previously generated. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penitence. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, these data indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective in preventing the development of metastatic prostate cancers.
2012-02-28 | GSE34839 | GEO
Project description:Squamous cell carcinoma (SCC) of lung is a devastating malignancy with no effective treatments, due to its complex genomic profile. Therefore, pre-clinical models mimicking its salient features are urgently needed. Here we describe mouse models bearing various combinations of genetic lesions predominantly found in human SCC. We show that Sox2 but not Fgfr1 overexpression in tracheobronchial basal cells combined with Cdkn2ab and Pten loss results in SCC closely resembling the human counterpart. Interestingly, Sox2;Pten;Cdkn2ab mice develop SCC with a more peripheral location when Club or Alveolar type 2 (AT2) cells are targeted. Our model highlights the essential role of Sox2 in promoting a squamous cell fate from different cells-of-origin and represents an invaluable tool for the developing better intervention strategies.
2016-11-09 | GSE78948 | GEO
Project description:NKX3.1 is an androgen-regulated, prostate-specific gene located on chromosome 8p21, a region frequently undergoing allelic loss in human prostate cancer. Mice deficient in NKX3.1 show signs of epithelial de-differentiation and develop dysplasia and prostatic intraepithelial neoplasia (PIN) that progresses to overt prostate cancer when combined with deletions of additional tumor suppressors such as PTEN or p27Kip1. Although NKX3.1 displays the typical features of an NK class homeobox transcription factor, mechanisms of NKX3.1-mediated tumor suppression remain insufficiently understood because neither the transcriptional program governed by NKX3.1 nor its interacting proteins have been comprehensively revealed. Adenoviruses were created that constitutively express either GFP alone, or GFP and NKX3.1 (Ad-GFP and Ad-GFP-NKX3.1 viruses, respectively). PrEC LH cells were infected with these viruses and were harvested at 7h and 10h after infection. Using affinity purification and tandem mass spectrometry, we have established an extensive NKX3.1 interactome. In particular, we found that the transcription factor forms stable complexes with the DNA repair proteins Ku70, Ku80, and PARP, interactions that provide a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of immortalized human prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human PIN devoid of NKX3.1. Pathway and network analyses suggested that NKX3.1 actuates a fundamental cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-Myc and interferon-STAT signaling and activation of tumor suppressor pathways.
2013-12-25 | E-GEOD-47030 | biostudies-arrayexpress