Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632852 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11790230.fastq.gz | Fastqsanger.gz | |||
| SRR11790231.fastq.gz | Fastqsanger.gz | |||
| SRR11790232.fastq.gz | Fastqsanger.gz | |||
| SRR11790233.fastq.gz | Fastqsanger.gz | |||
| SRR11790234.fastq.gz | Fastqsanger.gz |
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Project description:Aging of the mammary gland is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations within this organ. Here we leveraged the power of high-throughput single-cell RNA-sequencing (scRNA-seq) to generate a detailed transcriptomic atlas of young and aged murine mammary tissues, including both epithelial and stromal cell types. This analysis identified altered proportions and distinct gene expression patterns in multiple cell populations as a consequence of aging, independent of history of pregnancy and hormone cycle. In addition, we detected a rare luminal cell type that expresses both hormone-sensing and alveolar lineage markers as well as a unique gene expression signature. In addition, these cells exhibit a significant decrease in relative abundance with age. Overall, this high-resolution transcriptomic landscape reveals the effects of aging on normal mammary gland physiology and can serve as a valuable resource for understanding aging-associated susceptibility to breast cancer.
2020-12-29 | GSE150580 | GEO
Project description:Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary gland. Here, we leverage high-throughput single-cell RNA sequencing to generate a detailed transcriptomic atlas of young and aged murine mammary tissues. By analyzing epithelial, stromal, and immune cells, we identify age-dependent alterations in cell proportions and gene expression, providing evidence that suggests alveolar maturation and physiological decline. The analysis also uncovers potential pro-tumorigenic mechanisms coupled to the age-associated loss of tumor suppressor function and change in microenvironment. In addition, we identify a rare, age-dependent luminal population co-expressing hormone-sensing and secretory-alveolar lineage markers, as well as two macrophage populations expressing distinct gene signatures, underscoring the complex heterogeneity of the mammary epithelia and stroma. Collectively, this rich single-cell atlas reveals the effects of aging on mammary physiology and can serve as a useful resource for understanding aging-associated cancer risk.
| S-EPMC7898263 | biostudies-literature
Project description:The mammary epithelia are mainly composed of two distinct lineages, the basal and luminal cells. Due to the limitation of traditional transcriptome analysis of bulk mammary cells, the hierarchy and heterogeneity of mammary cells within these two lineages remain unclear. Hence, we have performed single cell RNA-seq on mammary epithelial cells of virgin and pregnant mice. Based on the respective gene expression profiles, we found mammary cells are highly heterogeneous and can be classified into distinct subgroups with signature markers. Besides, we identified and verified a rare CDH5+ subpopulation of basal lineage as quiescent mammary gland stem cells (MaSCs). Furthermore, knockout of Cdh5 in mouse mammary cells via CRISPR-Cas9 significantly impairs cell stemness and promotes the cell differentiation to luminal lineage. In addition, via pseudo-temporal analysis, we reconstructed the mammary epithelia developmental trajectory and revealed the relevant changes of gene expression and biological functions of mammary cells along the developmental process.
2018-02-09 | GSE110371 | GEO
Project description:Adipose stroma in the mouse mammary gland undergoes remodeling throughout the 5 stages of development. These include nulliparous (virgin;never been pregnant), pregnant, lactating, involuting and regressed. We used a microarry to determine the changes in gene expression during gland development. Mouse mammary glands were selected at three developmental stages for RNA extraction and hybridization on Affymetrix microarrays.
2013-12-06 | E-GEOD-53044 | biostudies-arrayexpress
Project description:Tissue resident macrophages in the mammary gland are found in close association with epithelial structures and within the adipose stroma, and are important for mammary gland development and tissue homeostasis. While epithelial-associated macrophages have been linked to ductal development, the contributions of stromal macrophages to mammary gland homeostasis remain unknown. Using transcriptional profiling, we identify a distinct resident stromal macrophage subpopulation that is characterized by expression of Lyve-1, a receptor for the extracellular matrix component hyaluronan. This subpopulation is enriched in genes associated with extracellular matrix remodeling and is found to be specifically associated with hyaluronan-rich regions within the mammary stroma. Furthermore, macrophage depletion leads to increased accumulation of hyaluronan-associated extracellular matrix in the mammary stroma. These results demonstrate the presence of a distinct subpopulation of macrophages and provide insights into the functional contributions of these macrophages to stromal homeostasis in the mammary gland.
2020-05-31 | GSE148207 | GEO
Project description:Adipose stroma in the mouse mammary gland undergoes remodeling throughout the 5 stages of development. These include nulliparous (virgin;never been pregnant), pregnant, lactating, involuting and regressed. We used a microarry to determine the changes in gene expression during gland development.
2013-12-06 | GSE53044 | GEO
Project description:Inactivation of RAR-b, which has been reported as a tumor suppressing gene by numerous studies, results in protective effect against the tumorigenesis induced by activated ErbB2. Moreover, tissue recombination indicates that the RAR-b deficient-microenvironment, rather than the RAR-b status of mammary epithelial cells, plays a key-determining role in the initiation and progression of the mammary carcinoma. Ablation of RAR-b extensively modulates the remodeling of stroma during tumor progression through suppressing the activation and transdifferetiation of myofibroblasts. RNA microarray has been employed to identify the gene expression signature in the mammary stroma of our RAR-b null animals. We want to find out the underlining mechanism of the protective effects resulted from Rarb abliton. A global gene expression profile of mouse mammary stroma was obtained on total RNA from the cleared mammary fat pads (stroma) of both RAR-b KO (n=3) and their wild type (n=3) littermates at the age of four weeks.
2010-12-18 | E-GEOD-19925 | biostudies-arrayexpress
Project description:Purpose: Leveraging genome-wide lineage-specific transcriptional profiling of human mammary luminal epithelial cells (LEPs) and myoepithelial cells (MEPs) to elucidate the molecular mechanisms underlying aging-associated breast cancer susceptibility. Methods: Human mammary luminal epithelial and myoepithelial cells were isolated from finite lifespan, non-immortalized human mammary epithelial cells (HMECs) derived from primary breast tissue of women across different age cohorts and breast cancer risk profiles. Transcriptional profiles of LEP and MEP cells were generated via RNA-sequencing performed on Illumina HiSeq 2500. RNA-Seq reads were trimmed using Trimmomatic software, and the processed reads were mapped back to the human genome (hg19) using TOPHAT2. Count matrices were generated using HTSeq. Results: Genome-wide loss of lineage fidelity is a hallmark of aging breast epithelia. Age-dependent differential expression occurred almost exclusively in luminal cells characterized by luminal epithelial cells of older women expressing markers normally expressed in myoepithelial cells. Luminal epithelial cells from histologically normal breast tissue from younger women who carry germline mutations in BRCA1, BRCA2, or PALB2 genes and who are considered to be clinically high risk for breast cancer also exhibited these hallmarks of accelerated aging. Furthermore, accelerated aging of these genetically high risk luminal epithelial cells could be predicted using a biological clock trained on gene expression and DNA methylation profiles of the luminal-specific ELF5 transcription factor. Conclusions: Our study shows that lineage-specific analysis is critical to understanding the molecular mechanisms underlying aging-associated cancer susceptibility. Our results suggest that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. Moreover, breast aging hallmarks identified in our study reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk.
2021-08-19 | GSE182338 | GEO
Project description:Specific deletion of Tgfbr2 in FSP1+ fibroblasts (Tgfbr2fspKO) induced development of SCC in forestomach with 100% penetrance. Tgfbr2fspKO mice die by 7 weeks with a median survival of 38 days (Log rank p<0.001). Examination of Tgfbr2fspKO forestomach between embryonic day 16 (E16) and 5 weeks of age suggested that hyperplasia began during week 3 and was followed by dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC). The aim of this study was to elucidate genetic aberrations in the tumor associated stroma and SCC tumor using array comparative genomic hybridization (CGH) analysis. Laser capture micro-dissection was performed using formalin-fixed, paraffin-embedded, 5 week old Tgfbr2fspKO forestomach tissues. Genetic loss of cyclin-dependent kinase inhibitor, Cdkn2a/ p16Ink4A was found in laser captured epithelia of all three Tgfbr2fspKO forestomachs. Surprisingly, no genetic change was seen in the tumor associated stroma. Examination of human esophageal SCC showed a down-regulation of TGFβ receptor 2 (TβRII) in the stromal fibroblasts as well as increased inflammation and DNA damage. Published literature showed that loss of Cdkn2a/p16Ink4A tumor suppressor is the common event in human ESCCs. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TβRII in the stroma. Laser capture microdissection of Tgfbr2flox/flox (n=3) and Tgfbr2fspKO (n=3) forestomach tissues was performed using an Arcturus XT (Life Technologies, CA, USA). Mouse background strain is C57Bl6. Frozen tissue sections on PEN membrane frame slides (Applied Biosystems) were H&E stained followed by dehydration using the standard protocol to improve visualization of the cells at the microscope. The epithelia and stroma were identified by morphology, captured using a low-power infrared laser pulse, and transferred onto a cap (Capsure™ Macro LCM Caps, Life Technologies). The DNA was extracted using a QIAamp DNA micro kit (Qiagen, CA, USA). Array-CGH was performed using test DNA from laser captured epithelia and stroma from Tgfbr2fspKO mice. Reference DNA was laser captured from the epithelia of normal forestomach of Tgfbr2flox/flox mice. DNA was labeled with Cy3 (test) or Cy5 (control) fluorescent dyes (Perkin Elmer, MA, USA) according to the BioPrime array CGH genomic labeling protocol (Invitrogen, Carlsbad, CA) and cleaned using Microcon YM-30 filters (Millipore, Billerica, MA). Hybridization was carried out using Mouse Genome CGH Microarray 4x180 K format from Agilent Technologies (Santa Clara, CA) according to CGH Procedures for Genomic DNA Analysis (Agilent Technologies). Slides were hybridized for 20 hours, washed, and scanned with an Agilent microarray scanner. Data was analyzed using Feature Extraction® and CGH Analytics® software packages (Agilent Technologies).
2012-12-06 | E-GEOD-42773 | biostudies-arrayexpress
Project description:Inactivation of RAR-b, which has been reported as a tumor suppressing gene by numerous studies, results in protective effect against the tumorigenesis induced by activated ErbB2. Moreover, tissue recombination indicates that the RAR-b deficient-microenvironment, rather than the RAR-b status of mammary epithelial cells, plays a key-determining role in the initiation and progression of the mammary carcinoma. Ablation of RAR-b extensively modulates the remodeling of stroma during tumor progression through suppressing the activation and transdifferetiation of myofibroblasts. RNA microarray has been employed to identify the gene expression signature in the mammary stroma of our RAR-b null animals. We want to find out the underlining mechanism of the protective effects resulted from Rarb abliton.
2010-12-18 | GSE19925 | GEO