Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA391297 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5725153.fastq.gz | Fastqsanger.gz | |||
| SRR5725154.fastq.gz | Fastqsanger.gz | |||
| SRR5725155.fastq.gz | Fastqsanger.gz | |||
| SRR5725156.fastq.gz | Fastqsanger.gz | |||
| SRR5725157.fastq.gz | Fastqsanger.gz |
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Project description:The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche. There are 2 samples sent in triplicates.
2011-08-31 | E-GEOD-24249 | biostudies-arrayexpress
Project description:Despite widespread knowledge that bone marrow-resident breast cancer cells (BMRCs) affect tumor progression, signaling mechanisms of BMRCs implicated in maintaining long-term dormancy have not been characterized. To overcome these hurdles, we developed a novel experimental model of tumor dormancy employing circulating tumor cells (CTCs) derived from metastatic breast cancer patients (de novo CTCs), transplanted them in immunocompromised mice, and re-isolated these cells from xenografted mice bone marrow (ex vivo BMRCs) and blood (ex vivo CTCs) to perform downstream transcriptomic analyses. Here we report that the balance between mTORC1 vs mTORC2 signaling regulates BMRC mitotic and/or dormancy characteristics.
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Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a M-bM-^@M-^\bi-lineageM-bM-^@M-^] differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition. Total of four treatments (HCC70 cells stably expressing shEZH2, shEED, or EZH2 cDNA, and MDA-MB-468 cells stably expressing shEZH2) were done in duplicates, each with its own control.
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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.
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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.
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