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Effect of nutritive conditions, adhesion and EMT on transcriptional profile of HMECs transduced by an oncogene RAS and SNAI1, SNAI2 or SNAI3

ABSTRACT: Oncogenic stress induces a global disturbance of cellular homeostasis and subsequently triggers the activation of tumour suppressor pathways. Energy capacity loss, redox state imbalance, and biosynthetic deficiency constitute the primary signals activating safeguard mechanisms, culminating in levels of stress that should not be compatible with infinite proliferative capacities of tumour initiating cells (TIC)s or cancer stem cells (CSC)s. Here, we show that the control of the glucocorticoid response by embryonic factors involved in mammary stemness5, 6 enables basal breast CSCs to not be faced with this oncogenic stress. The glucocorticoid response is thus correlated with stemness properties in basal breast cancers and is required for neoplastic transformation of mammary progenitors. This effect does not rely on hijacking tumour suppressor pathways, but on homeostatic buffering capacity. Through extensive analysis of homeostatic parameters and metabolic profiling, we show that the glucocorticoid response in mammary CSCs limits the “Warburg effect”, the ability of an oncogene to drive glucose fermentation in the presence of oxygen. The glucocorticoid response dampens glycolytic flow and maintains respiratory capacity resulting in reduction of mitochondria energisation. This enables CSCs to sustain carbon and nitrogen flows generated via glycolysis and the tricarboxylic acid cycle (TCA), required for homeostasis and anabolism maintenance. Overall, our results reveal the role of hormonal control of metabolic reprogramming in a CSC in rendering the cell permissive to oncogenic activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56164 | GEO | 2015/12/31

SECONDARY ACCESSION(S): PRJNA242613

REPOSITORIES: GEO

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Effect of nutritive conditions, adhesion and EMT on transcriptional profile of HMECs transduced by an oncogene RAS and SNAI1, SNAI2 or SNAI3

Project description:Oncogenic stress induces a global disturbance of cellular homeostasis and subsequently triggers the activation of tumour suppressor pathways. Energy capacity loss, redox state imbalance, and biosynthetic deficiency constitute the primary signals activating safeguard mechanisms, culminating in levels of stress that should not be compatible with infinite proliferative capacities of tumour initiating cells (TIC)s or cancer stem cells (CSC)s. Here, we show that the control of the glucocorticoid response by embryonic factors involved in mammary stemness5, 6 enables basal breast CSCs to not be faced with this oncogenic stress. The glucocorticoid response is thus correlated with stemness properties in basal breast cancers and is required for neoplastic transformation of mammary progenitors. This effect does not rely on hijacking tumour suppressor pathways, but on homeostatic buffering capacity. Through extensive analysis of homeostatic parameters and metabolic profiling, we show that the glucocorticoid response in mammary CSCs limits the âWarburg effectâ, the ability of an oncogene to drive glucose fermentation in the presence of oxygen. The glucocorticoid response dampens glycolytic flow and maintains respiratory capacity resulting in reduction of mitochondria energisation. This enables CSCs to sustain carbon and nitrogen flows generated via glycolysis and the tricarboxylic acid cycle (TCA), required for homeostasis and anabolism maintenance. Overall, our results reveal the role of hormonal control of metabolic reprogramming in a CSC in rendering the cell permissive to oncogenic activity. Immortalized human mammary epithelial cells (HMEC-hTERT cells) were infected with SNAIL retroviral expression constructs and an inducible form of RAS G12V. The gene expression profiles of the resulting cell lines, cultured in standard conditions, in limited nutrient supply or after plating them 16h in low-adherent (LA) conditions, were performed.

2015-12-31 | E-GEOD-56164 | biostudies-arrayexpress

Expression data of GFP-high or low cells of LGR5-GFP or KRT20-GFP knock-in human colorectal tumor organoids.

Project description:We analyzed gene expression of 3 lines LGR5-GFP, 2 lines KRT20-GFP knock-in colorectal tumor organdies. The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates LGR5+ CSCs targeting. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.

2017-03-30 | GSE83513 | GEO

Quantitative secretomics identifies ligand-receptor pairs in pancreatic cancer that mediate bidirectional crosstalk between cancer stem cells and nociceptors

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and most metastatic cancers in human. PDACs respond poorly to therapies, partly due to cancer stem cells (CSCs) that self-renew, survive chemotherapies, metastasise and replenish the tumour. Factors secreted by tumour cells mediate autocrine/paracrine crosstalk with surrounding cells contributing to the stem cell niche but are still insufficiently characterised. Here we used quantitative SILAC proteomics to identify secreted factors enriched in CSC secretome compared to non-CSCs. Among them were GDF15 and VGF, factors involved in cachexia and pain stimuli. GDF15 and VGF promoted CSC self-renewal and growth through autocrine effects. TGFβ/Activin signalling lowered GDF15 and VGF expression via SMAD2/3-SMAD4-SNON, switching to ATF4-CREB-mediated induction upon cell stress. Co-culture of PDAC-CSCs and hESC-derived neural cells for mimicking cellular crosstalk in PDAC revealed that paracrine signalling via GDF15/VGF promoted nociceptor formation and neurite outgrowth. In turn, Substance P from neurons supported CSC self-renewal, EMT/migration and clonal evolution that was also impacted by SMAD4 genetic status. Lastly, the serum levels of GDF15 and VGF were elevated in PDAC patients suggesting their utility as biomarkers for PDAC detection. Collectively, our data uncovered that cachexia and pain signalling factors mediate the crosstalk between CSCs and nociceptors.

2024-04-06 | PXD046026 | Pride

Cancer stem cell features shift during skin squamous cell carcinoma progression

2016-01-08 | GSE59439 | GEO

Cancer stem cell features shift during skin squamous cell carcinoma progression

Project description:Cancer stem cells (CSCs) play a key role in tumour growth and metastasis. Although an expansion of CSC population was previously described in advanced cutaneous squamous cell carcinoma (SCC), it remains unknown whether CSC regulatory mechanisms also change through tumour progression to promote malignancy. Here, we generate mouse models of skin SCCs to study alterations in CSC regulation over progression. We found that features of CSCs change at late stage of progression, correlating with a switch from epithelial to mesenchymal tumour shape. beta-catenin and EGFR signalling are down-regulated, whereas autocrine FGFR1 and PDGFR alpha pathways are up-regulated in CSCs of advanced tumours. Inhibition of FGFR and PDGFR signalling repress malignant SCCs growth and metastasis, respectively. An enhanced epithelial-to-mesenchymal transition (EMT) program and over-expression of PDGFR alpha and FGFR1 are observed in malignant human skin SCCs, suggesting that these pathways are also induced over human SCC progression. Therefore, uncover signalling pathways controlling CSCs at specific stage of progression may improve the selection of more accurate targeted therapeutic strategies according to tumour stage, blocking SCC relapse and metastasis. Mouse models of skin SCCs progression were first generated. For that, individual samples of spontaneous or DMBA-TPA induced skin SCCs generated in K14-HPV16 mice were orthotopically engrafted in immunodeficient mice and then serially transplanted, generating lineages in which the progression from WD-SCCs to PD-SCCs was observed. Then, tumour cells expressing CD34 and alpha 6-integrin, previously identified as cutaneous cancer stem cells, were isolated by flow cytometry-sorter from WD-SCCs and PD-SCCs of different tumour lineages. RNA extraction and hybridization on Affymetrix microarrays was carried out to compare whole gene profiling of these populations of CSCs.

2016-01-08 | E-GEOD-59439 | biostudies-arrayexpress

A Phase I/II Study of Active Immunotherapy With Cancer Stem Cells Vaccine for Colorectal Cancer

Project description:Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, the investigators examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity.Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement.CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring anti-tumor immunity.

| 2169532 | ecrin-mdr-crc

Expression data from subpopulations of Apc1638N/+ intestinal adeno tumors versus Apc1638N/+ / KRAS v12G intestinal adenocarcinomas tumors

Project description:Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in malignant Apc/KRAS–mutant carcinomas, they appear to be very rare (<10-6) in the benign Apc–mutant adenomas. In contrast, the Lin-CD24hiCD29+ subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active -catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins) are co-expressed together with stem cell genes (e.g. Lgr5) within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5+ stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing b-catenin intracellular stabilization. To identify molecular differences between stem-like and more differentiated (bulk) tumour cells from Apc1638N/+ and Apc1638N/+/KRASV12G intestinal adenomas and adenocarcinomas, we isolated total RNA from 104 Lin-CD24hiCD29+, Lin-CD24medCD29+/Lin-CD24loCD29+ and Lin- (bulk) tumour cells from 5 individual mice of each genotype (Apc1638N/+ and Apc1638N/+/KRASV12G). Total RNA samples were then employed to hybridize oligonucleotide microarrays (Affymetrix Mouse Genome 430A 2.0 Array) according to conventional protocols.

2013-10-01 | E-GEOD-47772 | biostudies-arrayexpress

C-terminally phosphorylated p27 regulates STAT3 transcriptional activation, inducing gene programs driving mammary duct and cancer stem cell expansion

Project description:While, p27 inhibits cell cycle in normal cells, in most cancers, p27 acquires oncogenic activities when phosphorylated by PI3K-activated kinases at T157 and T198 (p27pTpT). Mechanistically, these oncogenic functions of p27pTpT are poorly understood. Here, we show that p27pTpT promotes cancer stem cell (CSC) expansion through STAT3 both in vitro and in vivo. p27 phosphorylation increased STAT3 recruitment to chromatin to induce CSC self-renewal genes including MYC, the Notch ligand, JAG1, and ANGPTL4. We identify a feed-forward loop in which p27pTpT/STAT3 co-represses the Pyk2 inhibitor, PTPN12. Pyk2 in turn activates STAT3, driving CSCs expansion. p27pTpT is also shown to critically regulate mammary gland development. Mammary transgenic expression of phosphomimetic, cyclin-CDK binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis and hyperplasia, yielding primary and metastatic breast cancers. This supports a model in which p27pTpT co-regulates STAT3 to drive programs governing stem cell expansion or maintenance in normal and cancer tissues.

2024-04-19 | GSE233351 | GEO

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

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

Project description:Natural products (NP) encompass a rich source of bioactive chemical entities. Hence, NPs-derived compounds represent the majority of drugs currently approved to treat cancer. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (SCCRI025044), capable of selectively inhibiting human CSC function vs. normal stem cell (SC) counterparts. Biochemical and molecular studies revealed that SCCRI025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in human CSCs. SCCRI025044 impedes SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in human CSC biology.

2023-10-01 | GSE160551 | GEO

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