Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA289001 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Single-cell analysis reveals a stem cell program in human metastatic breast cancer cells (Human patients - mammary cells)
| PRJNA289006 | ENA
Project description:Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here we establish a robust method for identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA-sequencing and patient-derived xenograft (PDX) models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity, but micrometastases harbor a distinct transcriptome program conserved across PDX models that is highly predictive of poor survival in patients. Pathway analysis revealed mitochondrial oxidative phosphorylation (OXPHOS) as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of OXPHOS dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of OXPHOS in seeding and highlights its potential as a therapeutic target to prevent metastatic spread in breast cancer patients.
2020-02-20 | GSE123837 | GEO
Project description:Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site.
2020-12-22 | GSE151191 | GEO
Project description:Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to overcome the hurdles of metastatic cascade. However, the nutrient supply for maintaining the stemness potentials of metastatic cancer cells remains unknown. Here, we revealed that metastatic breast cancer cells maintain stemness and initiate metastasis upon detachment via uptaking and oxidating lactate. In detached metastasizing breast cancer cells, lactate was incorporated into tricarboxylic acid cycle and boosted oxidative phosphorylation, and then promoted the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate was uptake and oxidated in mitochondria by CD147/MCT1/LDHB complex, whose existence correlates to the stemness potentials and tumor metastasis in breast cancer patients. An intracellularly expressed single chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupted mitochondrial CD147/MCT1/LDHB complex, inhibited lactate-induced stemness potentials, depleted circulating breast cancer cells and reduced metastatic burden, suggesting a promising clinical application in reducing lactate-fueled metastasis.
2025-01-09 | PXD059617 |
Project description:Patients diagnosed with estrogen receptor (ER) positive breast cancer have a prolonged risk of distal metastatic recurrence to vital organs. Metastatic disease is incurable at present due to the development of treatment resistant cell populations. Here we used single-cell RNA sequencing to evaluate the transcriptome heterogeneity of ER+ breast cancer patient-derived xenografts (PDX) tropic for three common breast cancer metastatic sites – bone, brain, and liver – compared to primary tumors grown in the mammary fat pad. Metastatic cell populations at each location were phenotypically distinct from primary tumor cells with unique transcriptional programs indicative of signaling programs driven by specific transcription factors. Cells that metastasized to brain and liver tissue adopted gene expression programs indicative of the target organ microenvironments. Discerning the organ-specific phenotypic adaptations of metastatic ER+ breast cancer cells may help tailor appropriate therapies for individual patients and to each metastatic site.
2020-05-09 | GSE131007 | GEO
Project description:Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality1. Understanding metastasis initiation and progression is critical to develop new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumor cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumors.2 3-5 However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown.2 Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft (PDX) models of human breast cancer, we developed a highly sensitive FACS-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low vs. high metastatic burden. Metastatic cells from low-burden tissues were distinct due to their increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes. In contrast, metastatic cells from high-burden tissues were similar to primary tumor cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have significant tumor-initiating capacity, and differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and cMYC expression, which could be attenuated by treatment with cyclin dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, where metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.
2015-07-20 | GSE70554 | GEO
Project description:Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality1. Understanding metastasis initiation and progression is critical to develop new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumor cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumors.2 3-5 However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown.2 Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft (PDX) models of human breast cancer, we developed a highly sensitive FACS-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low vs. high metastatic burden. Metastatic cells from low-burden tissues were distinct due to their increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes. In contrast, metastatic cells from high-burden tissues were similar to primary tumor cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have significant tumor-initiating capacity, and differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and cMYC expression, which could be attenuated by treatment with cyclin dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, where metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.
2015-07-20 | GSE70552 | GEO
Project description:Mesenchymal stem/stromal cell engulfment reveals metastatic advantage in breast cancer
| PRJNA542295 | ENA
Project description:Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient tumor tissue and corresponding PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis protein expression was verified in a large gene expression data set of clinical breast cancers showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC growth and a potential therapeutic target for CSC as well as providing an additional mechanistic explanation for the observed benefit of statins in breast cancer treatment.
2019-07-02 | PXD011222 | Pride