KLF4, a gene regulating prostate stem cell homeostasis, is a barrier to malignant progression and predictor of a good prognosis in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA472603 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7203840_1.fastq.gz | Fastqsanger.gz | |||
| SRR7203840_2.fastq.gz | Fastqsanger.gz | |||
| SRR7203850_1.fastq.gz | Fastqsanger.gz | |||
| SRR7203850_2.fastq.gz | Fastqsanger.gz | |||
| SRR7203841_1.fastq.gz | Fastqsanger.gz |
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Project description:We propose that genes that control adult stem cell homeostasis in slowly turning over organs, such as prostate, control cancer fate. One such gene, KLF4, highly expressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation and controls the self-renewal of tumor initiating cells. KLF4 loss induces molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its signature containing downstream targets identify indolent tumors and predict recurrence-free survival in 2 prostate cancer cohorts. Thus, the link between normal stem cells and cancer control provides new approaches to improve prognosis and for identifying therapeutic targets for advanced cancer.
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Project description:There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. KLF4 loss induces the molecular features of aggressive cancer and converts PIN lesions to invasive sarcomatoid carcinomas; its re-expression in vivo reverses this process. Bioinformatic analysis links these changes to human cancer. KLF4 and its downstream targets make up a gene signature that identifies indolent tumors and predicts recurrence-free survival. This approach may improve prognosis and identify therapeutic targets for advanced cancer.
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Project description:We previously found that KLF4, a gene highly expressed in adult prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. To test whether this anti-cancer effect of KLF4 can also prevent prostate cancer-induced damage to the bone, we ablated KLF4 in human PC3 prostate cancer cells using CRISPR/Cas9-mediated genome editing and compared their behavior to null cells transduced with a DOX inducible KLF4 expression system. KLF4 re-expression inhibited growth of PC3 null cells in monolayer and as colonies in soft agar in a dose-dependent manner. When injected into the mouse femurs, PC3 null cells proliferated rapidly, forming very large, invasive and osteolytic tumors. Induction of KLF4 expression in PC3 null cells immediately after their intra-femoral inoculation blocked the development of tumors while preserving the normal bone architecture. KLF4 re-expression in established PC3 bone tumors inhibited osteolytic effects of PC3 null cells, preventing bone fractures and inducing a significant osteogenic response with regions of new bone formation. Transcriptome analyses of PC3 cells with no or high KLF4 expression revealed KLF4-dependent osteolytic or osteogenic transcriptional programs, respectively. Importantly, these KLF4-dependent functions significantly overlapped with metastatic prostate cancers in patients.
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Project description:Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based upon their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simean virus 40 T/t-antigens that is associated with the biologic behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb or BRCA1 expression, but not in tumors initiated through the overexpression of myc, ras, her2/neu, or Polyoma middle T oncogenes. Importantly, human breast, lung and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Since this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Since the these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in pre-clinical testing of therapies focused on these biologically important targets. Keywords: Genetically engineered mouse (GEM) models of cancer, epithelial carcinoma, SV40 T/t-antigen, survival predictor
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Project description:Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based upon their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simean virus 40 T/t-antigens that is associated with the biologic behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb or BRCA1 expression, but not in tumors initiated through the overexpression of myc, ras, her2/neu, or Polyoma middle T oncogenes. Importantly, human breast, lung and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Since this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Since the these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in pre-clinical testing of therapies focused on these biologically important targets. Keywords: Genetically engineered mouse (GEM) models of cancer, epithelial carcinoma, SV40 T/t-antigen, survival predictor Gene expression profiles from the SV40 T/t-antigen mouse models were compared with respect to specimen type (normal vs. tumor tissue), location of tumor (mammary, lung, prostate, seminal vesicle), and background strain of mice (FVB vs. C57BL/6). A three-way ANOVA model with one interaction effect (type X location) was fitted. Cancer genes that differ among all four tumor locations were identified, as those that had a significant interaction effect at the 0.001 level and showed at least a 2-fold change between the maximal and minimal mean tumor/normal ratio over the different locations (2638 cDNA probes). Based on the ANOVA model, differentially expressed genes between normal and tumor specimens within each tumor location were also identified, as those genes whose expression were significant at the 0.001 level and were at least 2-fold different compared to the mean expression ratio. Overall 3004 unique array features were selected using ANOVA. Further selection was applied based upon identification of differentially expressed genes between normal and tumor tissue for the three epithelial tumors (mammary, lung and prostate). The SV40 T/t-antigen oncogene-specific signature included genes similarly differentially expressed in each epithelial tumor (153 cDNA clones). In contrast, genes were included in a tissue-specific SV40 T/t-antigen tumor signature if they were found to be differentially expressed between the tumor and normal samples exclusively for one location. Two-hundred and eighty three, 220 and 999 cDNA clones were identified as specifically dysregulated in mammary, lung and prostate tumors, respectively).
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