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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160551 | GEO | 2023/10/01

REPOSITORIES: GEO

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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.

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BRD4 promotes distinct transcriptional programs in bulk and stem-like prostate tumor cells

Project description:Genetic knockdown or chemical inhibitors of BRD4 elicited different biological responses in bulk tumor cells in 2D cultures and CSC-enriched tumor-sphere cultures. Gene profiling revealed that BRD4 inhibition affected different sets of genes in two cell contexts. BRD4 drives a CSC-specific transcriptional programs that can be disrupted by chemical inhibitors causing exhaustion and elimination of prostate CSCs.

2017-09-06 | GSE103504 | GEO

Transcription profiling of human HMLER breast cancer cells treated with paclitaxel and salinomycin-treated HMLER breast cancer cells

Project description:Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs Experiment Overall Design: Experimentally transformed HMLER breast cancer cells were treated in culture with either paclitaxel (10nM) or salinomycin (1uM) for one week. There were three biologic replicates for each treatment condition.

2009-09-15 | E-GEOD-17215 | biostudies-arrayexpress

Gene expression profile of cancer stem cells (CSCs) isolated from wild type (WT) and Sfrp1-/- mice skin squamous cell carcinoma (SCC)

Project description:Sfrp1 is a Wnt inhibitor that is down regulated in various human cancers such as acute myeloid leukaemia, hepatocellular carcinoma, pancreatic, ovarian and breast cancer etc. Our study has shown that the loss of Sfrp1 in mouse skin leads to early tumor initiation with induced skin chemical carcinogenesis. Further, CSCs isolated from the Sfrp1-/- tumors showed increased in vivo tumorigenic potential with enhanced tumor propagating cell (TPC) frequency when injected into NOD/SCID mice. Hence, in order to understand the molecular mechanism involved in CSC regulation in the absence of sfrp1, we have performed microarray analysis on CSCs isolated from mice skin SCC. The data showed upregulation of genes involved in the regulation of tumor aggressiveness, metastasis and stemness in Sfrp1-/- CSCs as compared to WT CSCs. Our study has provided significant contribution to the existing knowledge of Sfrp1 by showing the uncharted role of Sfrp1 in tumor initiation and CSC regulation.

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Genome-wide analysis of gene expression by IFNβ in Transformed HMEC (Epithelial/non-CSC, Mesenchymal/CSC)

Project description:Triple Negative Breast Cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed Interferon/Signal Transducer and Activator of Transcription (IFN/STAT) gene signature and are often enriched for Cancer Stem Cells (CSCs). We have found that human mammary epithelial cells that undergo an Epithelial-to-Mesenchymal Transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with Interferon-Beta (IFNb) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and re-expression of CD24 (a surface marker for non-CSCs), concomitant with an epithelial-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated Interferon Stimulated Gene Factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFNb as gene expression profiling of patient derived TNBC tumors demonstrates that an IFNb Metagene signature correlates with improved patient survival, an immune response linked with Tumor Infiltrating Lymphocytes (TILs) and a repressed CSC Metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3, and that treatment with IFNb reduces CSC properties, suggesting a novel therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

2017-11-12 | GSE106782 | GEO

Expression data from paclitaxel and salinomycin-treated HMLER breast cancer cells

2009-08-20 | GSE17215 | 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

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Comparison of gene expression in CSCs (tumorspheres) vs non-CSCs (2D adherent condition) from A13A PDAC cell line [ATAC-seq]

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Expression profiles of CD24-/CD44+/ESA+ population in MDA-MB-231 and its highly metastatic variants.

Project description:Breast cancer is a curable disease if it is diagnosed at an early stage. However, only little options are left once the tumor is metastasized to distant organs, and more than 90% of breast cancer death is attributed to metastatic disease. The process of metastasis is highly complex and involves many steps for successful colonization of tumor cells at a target organ. According to the cancer stem cell (CSC) theory, which still remains a hypothesis, these metastatic cells must have stem cell-like capability for their self-renewal in addition to their invasive ability. Therefore, it has been predicted that a “metastatic stem cell”, which is distinct from a cancer stem cell, must exist in the primary tumor mass. To identify genes that are involved in metastasis of CSCs, we isolated CSC populations from a well-established model cell line of breast cancer, MDA-MB231, and that of highly metastatic variants, 231BoM-1833 and 231BrM-2a, using CD24, CD44 and EpCAM (ESA), which have been identified as surface markers for CSCs in breast cancers. Overall yield of CSCs from these cells ranged from 2% to 4%. We then performed global expression profile analysis for these CSCs using the Affymetrix Human Gene 1.0ST array. CSC populations (CD24-/CD44+/ESA+) from MDA-MB231, 231BoM-1833 and 231BrM-2a were isolated by magnetic-activated cell sorting (MACS) using specific antibodies to these surface markers. The total RNA was isolated from the CSC populations using the RNeasy RNA isolation kit (Qiagen). The RNA was then converted to cDNA and they were hybridized to the Human Gene 1.0ST chip (Affymetrix). The data was normalized using the RMA algorithm of the Expression Console software (Affymetrix). A comparison of transcriptional profiles was then performed in CSCs of highly metastatic cell lines (231BoM-1833 and 231BrM-2a) compared to the CSCs of MDA-MB-231.

2011-11-30 | E-GEOD-25976 | biostudies-arrayexpress

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