Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA289006 | ENA |
REPOSITORIES: ENA
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Project description:Single-cell analysis reveals a stem cell program in human metastatic breast cancer cells (PDX mice - cancer cells)
| PRJNA289001 | ENA
Project description:Cancer stem cells (CSCs) are proposed to be responsible for metastatic dissemination and clinical relapse in a variety of cancers. Analogies between CSCs and normal tissue stem cells (SC) has led to the notion that CSCs often co-opt the normal SC program of their tissue-of-origin. The cell-biological program termed epithelial-mesenchymal transition (EMT) has been found to encourage entrance of normal and neoplastic mammary cells into the corresponding SC states. Using genetically engineered knock-in reporter mouse lines, we demonstrate that in the murine mammary lineage, the paralogous EMT-inducing transcription factors Snail and Slug, are selectively exploited by CSCs and normal SCs respectively. Slug, when expressed at physiological levels, only activates a partial EMT program and is dispensable in CSCs. In contrast, Snail drives a far more complete transition into the mesenchymal state and controls both tumor-initiation and metastatic dissemination. Consistent with their functional distinctions, Snail controls far more target genes than Slug, and their distinct functions are determined by their divergent N-terminal domains. Our findings underscore fundamental distinctions between the SC program operating in normal and neoplastic SCs, and hint for potential avenues of selective therapeutic elimination of breast CSCs. We sought to understand differential ability to activate the EMT program in breast cancer cells by transcription factors Snail and Slug. Hence, we mapped genome-wide Snail and Slug binding sites in murine MMTV-PyMT breast cancer cell lines that express high level of Snail or high level of Slug respectively. Specifically, we performed Snail ChIP seq in the mesenchymal pBl.3G cells, and Slug ChIP-seq in the epithelial pBl.1G cells.
2015-09-02 | E-GEOD-61198 | biostudies-arrayexpress
Project description:The capacity of stem cells to maintain and regenerate organs is critically dependent on the niche, a complex signaling microenvironment that sustains and regulates stem cell activity. Niche function in the mammary gland must integrate local homeostatic activities with hormonally regulated events, such as pregnancy or the onset of puberty. In the human disorder CPHD (combined pituitary hormone deficiency) breast growth defects at puberty are associated with mutations disrupting the transcription factor, GLI2. Here we find that Gli2 functions in mouse mammary stromal cells to shape a niche signaling program that sustains mammary epithelial stem cells. Ablation of Gli2 in stromal cells thus leads to a disorganized mammary gland, associated with collapse of the niche signaling environment, with a five-fold decrease in functional mammary stem cell activity, and with attenuated response to the mammatrophic hormones estrogen and growth hormone. Consistent with a niche defect, aspects of Gli2-deficient mammary gland architecture can be rescued by local supplementation with IGF and WNT protein signals. Our findings thus identify GLI2 as a critical coordinator of local and hormonal influences on the niche signaling program, and suggest that mammary pathogenesis in CPHD patients results from dysfunction of the mammary epithelial stem cell niche. We used microarrays to identify gene expression signatures associated with stromal Gli2 expression
2015-03-13 | GSE66820 | GEO
Project description:The Wnt/beta-catenin signalling pathway plays a central role in mammary stem cell homeostasis and in breast cancer. We employed the CD29hiCD24+ cell surface antigens to identify a subpopulation of mammary CSCs from Apc1572T/+, a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer in man. The MaCSCs are capable of recapitulating tumorigenesis when transplanted at low multiplicities in vivo, and of forming self-renewing organoids in vitro. Expression profiling of the different subpopulations sorted from normal and neoplastic mammary tissues revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling was found to be activated in the subpopulation encompassing normal mammary stem cells, though to a lesser degree than in the tumor cells. By comparing normal with cancer mouse mammary compartments, we were able to derive a MaCSC-specific signature composed of human orthologous genes able to predict poor survival, relapse and distant metastasis in human breast cancer. Finally, upon intravenous injection, only MaCSCs among the different tumor cell subpopulations are able to form metastatic lesions in a broad spectrum of anatomical sites. Overall, our data indicate that constitutive Wnt signaling activation interferes with mammary stem cell homeostasis leading to metaplasia and basal-like adenocarcinomas. The objective was to compare the: i) expression profiles between normal adult mammary stem cells and tumor cancer stem cells identified by Lin-CD29hiCD24+; ii) expression profile between adult stem cells and their differentiated counterparts both in normal and in tumor tissue to generate a cancer stem cell signature that can be used to compare with mammary human tumor expression data to predict survival and prognosis. To this aim five independent mammary adenocarcinomas from C57BL6/J Apc+/1572T mice and three independently isolated pools of mammary glands from C57BL6/J Apc+/+ mice were employed to sort 10,000 cells of each of the following populations: Lin-, Lin-CD29+CD24+ and Lin-CD29hiCD24+.
2013-08-29 | E-GEOD-40704 | biostudies-arrayexpress
Project description:The Wnt/beta-catenin signalling pathway plays a central role in mammary stem cell homeostasis and in breast cancer. We employed the CD29hiCD24+ cell surface antigens to identify a subpopulation of mammary CSCs from Apc1572T/+, a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer in man. The MaCSCs are capable of recapitulating tumorigenesis when transplanted at low multiplicities in vivo, and of forming self-renewing organoids in vitro. Expression profiling of the different subpopulations sorted from normal and neoplastic mammary tissues revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling was found to be activated in the subpopulation encompassing normal mammary stem cells, though to a lesser degree than in the tumor cells. By comparing normal with cancer mouse mammary compartments, we were able to derive a MaCSC-specific signature composed of human orthologous genes able to predict poor survival, relapse and distant metastasis in human breast cancer. Finally, upon intravenous injection, only MaCSCs among the different tumor cell subpopulations are able to form metastatic lesions in a broad spectrum of anatomical sites. Overall, our data indicate that constitutive Wnt signaling activation interferes with mammary stem cell homeostasis leading to metaplasia and basal-like adenocarcinomas. The objective was to compare the: i) expression profiles between normal adult mammary stem cells and tumor cancer stem cells identified by Lin-CD29hiCD24+; ii) expression profile between adult stem cells and their differentiated counterparts both in normal and in tumor tissue to generate a cancer stem cell signature that can be used to compare with mammary human tumor expression data to predict survival and prognosis. To this aim five independent mammary adenocarcinomas from C57BL6/J Apc+/1572T mice and three independently isolated pools of mammary glands from C57BL6/J Apc+/+ mice were employed to sort 10,000 cells of each of the following populations: Lin-, Lin-CD29+CD24+ and Lin-CD29hiCD24+.
2013-08-29 | E-GEOD-40702 | biostudies-arrayexpress
Project description:The Wnt/beta-catenin signalling pathway plays a central role in mammary stem cell homeostasis and in breast cancer. We employed the CD29hiCD24+ cell surface antigens to identify a subpopulation of mammary CSCs from Apc1572T/+, a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer in man. The MaCSCs are capable of recapitulating tumorigenesis when transplanted at low multiplicities in vivo, and of forming self-renewing organoids in vitro. Expression profiling of the different subpopulations sorted from normal and neoplastic mammary tissues revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling was found to be activated in the subpopulation encompassing normal mammary stem cells, though to a lesser degree than in the tumor cells. By comparing normal with cancer mouse mammary compartments, we were able to derive a MaCSC-specific signature composed of human orthologous genes able to predict poor survival, relapse and distant metastasis in human breast cancer. Finally, upon intravenous injection, only MaCSCs among the different tumor cell subpopulations are able to form metastatic lesions in a broad spectrum of anatomical sites. Overall, our data indicate that constitutive Wnt signaling activation interferes with mammary stem cell homeostasis leading to metaplasia and basal-like adenocarcinomas.
2013-08-29 | GSE40704 | GEO
Project description:The Wnt/beta-catenin signalling pathway plays a central role in mammary stem cell homeostasis and in breast cancer. We employed the CD29hiCD24+ cell surface antigens to identify a subpopulation of mammary CSCs from Apc1572T/+, a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer in man. The MaCSCs are capable of recapitulating tumorigenesis when transplanted at low multiplicities in vivo, and of forming self-renewing organoids in vitro. Expression profiling of the different subpopulations sorted from normal and neoplastic mammary tissues revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling was found to be activated in the subpopulation encompassing normal mammary stem cells, though to a lesser degree than in the tumor cells. By comparing normal with cancer mouse mammary compartments, we were able to derive a MaCSC-specific signature composed of human orthologous genes able to predict poor survival, relapse and distant metastasis in human breast cancer. Finally, upon intravenous injection, only MaCSCs among the different tumor cell subpopulations are able to form metastatic lesions in a broad spectrum of anatomical sites. Overall, our data indicate that constitutive Wnt signaling activation interferes with mammary stem cell homeostasis leading to metaplasia and basal-like adenocarcinomas.
2013-08-29 | GSE40702 | GEO
Project description:Macrophages have been implicated in breast cancer progression and metastasis, but relatively little is known about the genes and pathways that are involved. Using a conditional allele of Ets2 in the mouse, we have identified Ets2 as a critical gene in tumor associated macrophages (TAMs) that specifically promotes mammary tumor metastasis. Loss of Ets2 in TAMs decreased the frequency and size of lung metastases without impacting primary tumor burden. Expression profiling of isolated tumor macrophages established that Ets2 deficiency resulted in the de-repression of a defined set of anti-angiogenic genes. Activation of this transcriptional program correlated with decreased angiogenesis in metastatic tumors and decreased metastatic growth. Comparison of this Ets2-specific TAM expression profile with human breast cancer profiles revealed a macrophage gene expression signature that could predict overall survival of estrogen receptor negative patients. In summary, we have identified a critical factor, Ets2, in TAMs that represses a transcriptional program to promote the growth of mammary tumor metastases in the lung. Breast TAMs were isolated from early-stage PyMT-induced mammary tumors expressing Ets2 and also from the tumors with Ets2-deficient TAMs. Since macrophages have also been implicated in normal mammary gland remodeling, normal remeodeling macrophages were also purified from females expressing Ets2 and the ones where Ets2 is deleted in the macrophages. One RNA sample was extracted from each genetic group for gene-expression profiling.
2010-01-05 | E-GEOD-12863 | biostudies-arrayexpress
Project description:Cancer stem cells (CSCs) are proposed to be responsible for metastatic dissemination and clinical relapse in a variety of cancers. Analogies between CSCs and normal tissue stem cells (SC) has led to the notion that CSCs often co-opt the normal SC program of their tissue-of-origin. The cell-biological program termed epithelial-mesenchymal transition (EMT) has been found to encourage entrance of normal and neoplastic mammary cells into the corresponding SC states. Using genetically engineered knock-in reporter mouse lines, we demonstrate that in the murine mammary lineage, the paralogous EMT-inducing transcription factors Snail and Slug, are selectively exploited by CSCs and normal SCs respectively. Slug, when expressed at physiological levels, only activates a partial EMT program and is dispensable in CSCs. In contrast, Snail drives a far more complete transition into the mesenchymal state and controls both tumor-initiation and metastatic dissemination. Consistent with their functional distinctions, Snail controls far more target genes than Slug, and their distinct functions are determined by their divergent N-terminal domains. Our findings underscore fundamental distinctions between the SC program operating in normal and neoplastic SCs, and hint for potential avenues of selective therapeutic elimination of breast CSCs.
2015-09-02 | GSE61198 | GEO