Project description:PTEN is one of the most altered tumor suppressor genes in human prostate cancer. Prostate specific-Pten-deficient mouse models develop prostate cancer eventually progressing to CRPC, also due to alterations of the tumor immune infiltrate.
Project description:Prostate cancer (PCa) is one of the most common cancers diagnosed in men in the world. The majority of patients develop resistant to androgen deprovation therapy, leading to castration-resistant PCa (CRPC). CRPC have a poorer prognosis and developing metastasis compared to hormone-sensitive PCa. To chracterize for new regulators of progression from HSPC to CRPC, LNCaP and C4-2 cells were selected as HSPC and CRPC, respectively. A comparative assessment of proein expression characteristics between two cells may provide insight into the regulatory landscape of CRPC.
Project description:Gene expression data from Agilent-014850 4x44K human expression array for CRPC Prostate Cancer study with Xenograph data. RNA was isolated using the mirVana total RNA protocol (part #AM1560, Ambion, Austin, TX). RNA integrity was verified using a 2100 Bioanalyzer (part #G2938A) with nano chips (parts #5067-15101 and #G4411B; Agilent Technologies, Alto, CA). RNA concentrations were determined using a Nanodrop spectrophotometer (Thermo Scientific, Wilmington, DE). Tumor messenger RNA expression was assessed using a human whole-genome oligo TMA kit from Agilent (prod #G4112F) according to the manufacturer’s protocol and as described previously. In the Characteristics field, we have the notation like "Pt Dxed in 2001; hormone Tx; chemo Tx 2002; HRPC by 2002". That means the patient was admitted in 2001, did hormone and chemo treatment in 2002, and HRPC 2002. They are standard prostate cancer treatments.
Project description:To investigate the mechanisms underlying castration-resistant prostate cancer (CRPC) development, we used a prostate cancer (PCa) allograft mouse model. In this model, an androgen-dependent (AD) mouse prostate cancer cell line, Myc-CaP, was used. Myc-CaP cells can grow as primary prostate tumors (PPC) in immune competent FVB mice in an AD manner, when host mice are castrated, Myc-CaP allografts shrink (shrunken prostate tumor, S-PC), and later re-grow and become AR-positive CRPC. To compare the gene expression of different stage of PCa, primary cells from PPC, S-PC, and CRPC were isolated and purified. We used RNA-seq to detail the global programme of gene expression underlying castration-resistant prostate cancer (CRPC) development and identified distinct classes of up-regulated or down-regulated genes during this process.
Project description:In order to identify the contribution of Lkb1 loss to Pten driven prostate cancer progression, we engineered a prostate conditional mutant mice in which was induced the loss of Lkb1 in combination with heterozygous loss of the prostate tumor suppressor Pten (Ptenpc+/- Lkb1pc-/-). This mouse model developed metastatic prostate squamous cell carcinoma. We compared this tumor type with the adenocarcinomas developed in Ptenpc-/- Lkb1pc+/+ mice. We carried out microdissection and RNA extraction of tumor tissues embedded in paraffin of Ptenpc+/- Lkb1pc-/- and Ptenpc-/- Lkb1pc+/+. To distinguish between early and late phenotype of prostate squamous cell carcinoma, we compared Ptenpc+/- Lkb1pc-/- tumor tissues collected at the age of six and ten months of age among them and with Ptenpc-/- Lkb1pc+/+ mouse prostate tissue.
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.
Project description:A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor Fosl1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in the aggressive mesenchymal stem-like prostate cancer (MSPC) subtype recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258—focused on Fosl1/AP-1 and PIM kinases, respectively—effectively suppress both the progenitor properties and the growth of mouse and human MSPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.