Article

Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells

Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA.
Cell stem cell (Impact Factor: 22.27). 05/2008; 2(4):333-44. DOI: 10.1016/j.stem.2008.02.009
Source: PubMed

ABSTRACT

Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.

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    • "In contrast to adult stem cells, endogenous MYC prevents differentiation of embryonic stem cells, and enhanced expression of MYC facilitates the generation of induced pluripotent stem cells (Cartwright et al., 2005; Takahashi and Yamanaka, 2006). Consistent with these observations, meta-analyses show that deregulation of MYC enhances expression of genes characteristic of embryonic stem cells but inhibits expression of genes expressed in adult stem cells (Ben-Porath et al., 2008; Wong et al., 2008). "
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    ABSTRACT: In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/ TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors.
    No preview · Article · Dec 2015 · Cancer Cell
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    • "Gene-expression levels in breast tumors have been shown to reflect functional germline variation. For example, expression patterns in tumors from patients with germline BRCA1 and BRCA2 variants exhibit distinctive patterns compared to tumors from individuals who do not carry these mutations14151617181920212223242526. Accordingly, we hypothesized that geneexpression-levels in normal cells should be similar across many women who develop FBC and thus indicative of disease risk, even though the underlying genetic and epigenetic variation may vary considerably across these women. "
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    ABSTRACT: Background Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person’s risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC. Methods We profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women (197 total). We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers. Results Our multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have “high” risk by our model would have an estimated 2.4 times greater odds of developing familial breast cancer than individuals deemed to have “low” risk. Conclusions Together, these findings suggest that gene-expression levels in peripheral blood cells reflect genomic variation associated with breast cancer risk and that such data have potential to be used as a non-invasive biomarker for familial breast cancer risk. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0145-6) contains supplementary material, which is available to authorized users.
    Full-text · Article · Nov 2015 · BMC Medical Genomics
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    • "To study the functional relevance of this signature, we performed a Gene Set Enrichment Analysis (GSEA). GSEA identified several gene signatures (Supplementary Figure 1), including a gene signature associated with stem cells ( " Wong_Adult_Tissue_Stem_ Module " ) (Figure 6B)[37]. Figure 6Cdisplays all the genes included in the GSEA analysis after the filtering performed by the program; significant differences were observed between the PIWIL1-positive and PIWIL1- negative group. "
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    ABSTRACT: The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression.
    Preview · Article · Jan 2015 · Oncotarget
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