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The biological and molecular heterogeneity of breast cancers correlate with their cancer stem cell content

ABSTRACT: Pathways that govern normal stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SC (hNMSCs), from cultured mammospheres, based on their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. We demonstrated that PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancers. By using markers of the hNMSC signature, we could prospectively isolate SCs from the normal gland and from breast tumors. Poorly-differentiated aggressive (G3) cancers displayed higher content of prospectively isolated cancer SCs, than well-differentiated less aggressive (G1) cancers. By comparing G3 and G1 tumors in xenotransplantation experiments, we directly demonstrated that G3s are enriched in cancer SCs. Our data support the notion that the heterogeneous phenotypical and molecular traits of human breast cancers are a function of their SC content.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18931 | GEO | 2009/11/07

SECONDARY ACCESSION(S): PRJNA121041

REPOSITORIES: GEO

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The biological and molecular heterogeneity of breast cancers correlate with their cancer stem cell content

Project description:Pathways that govern normal stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SC (hNMSCs), from cultured mammospheres, based on their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. We demonstrated that PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancers. By using markers of the hNMSC signature, we could prospectively isolate SCs from the normal gland and from breast tumors. Poorly-differentiated aggressive (G3) cancers displayed higher content of prospectively isolated cancer SCs, than well-differentiated less aggressive (G1) cancers. By comparing G3 and G1 tumors in xenotransplantation experiments, we directly demonstrated that G3s are enriched in cancer SCs. Our data support the notion that the heterogeneous phenotypical and molecular traits of human breast cancers are a function of their SC content. Epithelial cells, from reductive mammoplasties, labeled with PKH26 (Sigma, 10-7 M, 5 min) and subjected to FACS analysis using a FACS Vantage SE flow cytometer (Becton&Dickinson) to yield PKH-POS and PKH-NEG cells, were prepared for RNA extraction and hybridization on Affymetrix microarrays. Three independent pools of cells were used, and six Gene Expression Arrays were obtained. No replicates are available.

2009-11-06 | E-GEOD-18931 | biostudies-arrayexpress

miR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer

Project description:Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we found that the miR-146 family is linked to SC identity, since: i) their expression is very high in SCs/CSCs from human/mouse primary mammary tissues; correlates with the basal-like breast cancer subtype, which typically has a high CSC content; and specifically distinguishes cells with SC/CSC identity; ii) miR-146 depletion reduces SC/CSC self-renewal in vitro and the number of tumor-initiating cells in vivo. Analysis of the transcriptional effects of miR-146 in breast SC-like cells revealed a complex network of highly connected miR-146 targets related to quiescence, transcription and metabolic pathways (one-carbon pool, purine synthesis and folate metabolism). As predicted by our analysis, SCs/CSCs display innate resistance to anti-folate therapy that can be reversed by miR-146 depletion, unmasking a “hidden vulnerability” that could be exploited for the development of anti-CSC therapies.

2020-01-21 | GSE131876 | GEO

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.

2015-09-02 | E-GEOD-61198 | biostudies-arrayexpress

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

2015-09-02 | GSE61198 | GEO

Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn's disease in a retinoic acid-deficient manner

Project description:Stromal cell (SC) contributions to intestinal inflammation are inadequately understood. Here we show that CD90+vimentin+SMA- SCs isolated from Crohn’s disease intestine (Crohn’s SCs) displayed higher levels of spontaneously released and microbiota-induced inflammatory mediators, including IL-6 and TGF-b, and surface adhesion molecules, than SCs isolated from healthy intestine (Normal SCs). Comparative transcriptome analysis confirmed the predominance of upregulated inflammatory response and cytokine signaling genes and pathway molecules in Crohn’s SCs. Importantly, intestinal SCs provided retinoic acid (RA), which regulated DC maturation, and in an in vitro cross-talk system E. coli LF82-stimulated Crohn’s SCs promoted differentiation of more inflammatory TNFhi/IL-12lo/RAlo DCs and IFN-ghi/IL-17hi effector T cells than Normal SCs. Explaining this finding, Crohn’s SCs synthesized less RA and expressed more retinaldehyde reductase DHRS3, which inhibits retinol conversion to retinal, than Normal SCs. Our findings uncover microbe-SC crosstalk in which mucosal SCs initiate and perpetuate DC-driven T-cell-mediated inflammation in Crohn’s disease.

2024-07-21 | GSE178994 | GEO

Schwann cell plasticity regulates neuroblastic tumor cell differentiation

Project description:The remarkable plasticity of Schwann cells (SCs) is essential for nerve regeneration but also contributes to neuropathies and cancer progression. It has not yet been investigated whether the adaptive potential of SCs is manifested in stromal, tumor associated SCs characteristically found within a benign subtype of neuroblastic tumors (NBTs). We here performed transcriptome profiling of human NBTs, rich and poor in SC stroma, as well as human injured nerves, rich in repair SCs, revealing that stromal SCs exhibit a repair SC characteristic gene expression signature. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on NBT cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of aggressive NBT cells. EGFL8 expression further correlated with favorable tumor stage and increased patient survival. Our findings suggest that stromal SCs exert nerve repair associated functions in the tumor-environment and underline the therapeutic value of SC-derived factors for aggressive, SC stroma-poor NBTs.

2021-01-13 | PXD018267 | Pride

Schwann cell plasticity regulates neuroblastic tumor cell differentiation - phosphoproteomics

2021-01-04 | PXD022217 | Pride

Mouse Muscle Stem Cell Proteome during Activation and CPEB1 Dependent Proteome in Mouse Muscle Stem Cell

Project description:Muscle Stem Cells or satellite cells (SCs) are required for muscle regeneration. In resting muscles, SCs are kept in quiescence. After injury, SCs undergo rapid activation, proliferation and differentiation to repair damaged muscles. The transcriptome alteration during SC activation is well characterized. While transcriptome is not exactly represent proteome because of post-transcriptional regulations such as miRNA induced gene silencing. However, little is known about SC proteome. We obtained quisecent SCs (QSCs) and freshly isolated SCs (fiSCs, early activated SCs) and activated SCs (ASCs) for high resolution mass spectrometry Bruker timsTOF Pro. Thus, we uncovered the QSC proteome. By comparison of QSC proteome to fiuSCs proteome or ASCs proteome, we identified the pathways that are differentially expressed between them. Forthermore, we characterized a translational regulator CPEB1 reprogrammed translation landscape for SC activation.

2021-11-05 | PXD018865 | Pride

Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas

Project description:Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism arrays in 57 (31 CCCs, 14 SCs, and 12 ECs) and expression microarrays in 55 epithelial ovarian cancers (25 CCCs, 16 SCs, and 14 ECs), and then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%) (P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the others (CCC-1and CCC-3) (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%) (P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub-classification of CCC, and might provide useful information on prognosis. Gene expression in 55 epithelial ovarian cancers (25 CCCs, 16 SCs, and 14 ECs) was analyzed by Affymetrix U133plus2 array.

2015-05-11 | E-GEOD-65986 | biostudies-arrayexpress

3 days injured in vivo ASCs proteome

Project description:Muscle Stem Cells or satellite cells (SCs) are required for muscle regeneration. In resting muscles, SCs are kept in quiescence. After injury, SCs undergo rapid activation, proliferation and differentiation to repair damaged muscles. The transcriptome alteration during SC activation is well characterized. While transcriptome is not exactly represent proteome because of post-transcriptional regulations such as miRNA induced gene silencing. However, little is known about SC proteome. We obtained in vivo activated SCs (ASCs) from 3 days post injured muscles for high resolution mass spectrometry Bruker timsTOF Pro. Compared with QSC proteome,, we identified the pathways that are differentially expressed between them.

2021-11-04 | PXD023656 | Pride

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