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Cell state transitions regulated by Slug are critical for tissue regeneration and tumor initiation [Agilent microarray samples]

ABSTRACT: Alterations that perturb differentiation and cell state transitions can lead to defects in development, function and the genesis of cancer. Studying cellular plasticity at high resolution and in real time has proven difficult using existing methods. Here, we use a quantitative approach to gain insights into cell state dynamics of normal mammary epithelial cells (MECs) and validate the model's predictions in vivo. In the absence of Slug/SNAI2, basal mammary progenitor cells transition into a luminal differentiation state, while luminal progenitor cells proliferate and expand; these changes result in abnormal mammary architecture and defects in tissue function. Loss of Slug also disrupts cellular plasticity leading to defects in tissue regeneration and the initiation of cancer. Mechanistically, Slug promotes cellular plasticity by recruiting the chromatin modifier, LSD1 (lysine specific demethylase 1), to promoters of lineage specific genes to represses transcription. Together, these finding demonstrate that Slug is necessary for cellular adaptation during tissue development and regeneration, and that transitioning back into a more primitive stem-like state is a prerequisite for tumor initiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54713 | GEO | 2014/06/23

SECONDARY ACCESSION(S): PRJNA237521

REPOSITORIES: GEO

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Cell state transitions regulated by Slug are critical for tissue regeneration and tumor initiation [Agilent microarray samples]

Project description:Alterations that perturb differentiation and cell state transitions can lead to defects in development, function and the genesis of cancer. Studying cellular plasticity at high resolution and in real time has proven difficult using existing methods. Here, we use a quantitative approach to gain insights into cell state dynamics of normal mammary epithelial cells (MECs) and validate the model's predictions in vivo. In the absence of Slug/SNAI2, basal mammary progenitor cells transition into a luminal differentiation state, while luminal progenitor cells proliferate and expand; these changes result in abnormal mammary architecture and defects in tissue function. Loss of Slug also disrupts cellular plasticity leading to defects in tissue regeneration and the initiation of cancer. Mechanistically, Slug promotes cellular plasticity by recruiting the chromatin modifier, LSD1 (lysine specific demethylase 1), to promoters of lineage specific genes to represses transcription. Together, these finding demonstrate that Slug is necessary for cellular adaptation during tissue development and regeneration, and that transitioning back into a more primitive stem-like state is a prerequisite for tumor initiation. reference x sample

2014-06-23 | E-GEOD-54713 | biostudies-arrayexpress

Project description:Cell state transitions regulated by Slug are critical for tissue regeneration and tumor initiation

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Distinct EMT programs control normal stem cells and cancer stem cells of mammary tissue

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.

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Gene expression profiles of young and aged mammary epithelial and stromal cell populations from Wild Type and Slug/Snai2-null mice

Project description:This experiment shows RNA-Seq gene expression profiles of Wild Type and Slug/Snai2-null luminal, basal, and stromal mammary cell populations from young (3 mo) and aged (12 mo) mice.

2019-07-09 | GSE132127 | GEO

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Project description:Cell state transitions regulated by Slug are critical for tissue regeneration and tumor initiation [Agilent microarray samples]

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Distinct EMT programs control normal stem cells and cancer stem cells of mammary tissue

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Expression data from sorted control and Pygo2-null mouse mammary stem/basal cells

Project description:Skin-mammary specific knockout (SSKO) of Pygo2 (K14-cre; Pygo2 flox/-) , a WNT signaling co-activator, results in defective mouse mammary gland development. The FACS sorted mammary stem cell (MaSC)/basal population from Pygo2 SSKO mammary gland displays biased differentiation towards luminal/alveolar lineage in vitro, and reduced regeneration rate of new mammary gland in vivo To gain the insight into gene expression profiles in control and Pygo2 SSKO mammary epithelial cells (MECs), we sorted the freshly isolated mouse MECs into MaSC/basal (Lin-CD29hiCD24+) and mature luminal population (Lin-CD29lowCD24+CD61-), and extract total RNA for cDNA microarray analysis

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Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=5, LMC) compared to resting, non-lactating human breast tissue (n=3, NMC). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. This data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.

2021-12-10 | E-MTAB-10855 | biostudies-arrayexpress

10x scRNA-seq analysis of a human milk cell sample compared to a non-lactating breast tissue sample

Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=1, LMC) compared to resting, non-lactating human breast tissue (n=1, NMC, ran over 3 lanes of a 10x Genomics chip). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic hematopoietic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. This data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.

2021-12-10 | E-MTAB-10885 | biostudies-arrayexpress

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