Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522885 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8585570.fastq.gz | Fastqsanger.gz | |||
| SRR8585580.fastq.gz | Fastqsanger.gz | |||
| SRR8585590.fastq.gz | Fastqsanger.gz | |||
| SRR8585561.fastq.gz | Fastqsanger.gz | |||
| SRR8585571.fastq.gz | Fastqsanger.gz |
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Project description:Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation.
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Project description:Circulating Tumor Cells Clustering Triggers DNA Methylation Changes to Enable Metastasis Seeding
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Project description:Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which has been proposed as the major determinant of processes involving tumor invasion and metastasis. To study whether circulating DNA (cirDNA) in blood plasma reflects the changes that the tumor cells undergo under IH conditions, we used a xenografted murine model. Mice engrafted with TC1 epithelial lung and controls were exposed to IH or room air (RA) conditions. Plasma cirDNA amounts were significantly increased in mice exposed to IH (p<0.05). We found a significant correlation between plasma cirDNA concentration and tumor size, weight and invasiveness (p<0.05). Using a microarray-based approach, we identified 2,094 regions showing significant differential cirDNA modifications. System biology analysis revealed an association with molecular pathways misregulated in cancer progression and with distal and TSS-associated transcription factor binding sites. We detected clusters of highly variable regions in chromosomes 7, 13, 14 and X, which may highlight hotspots for DNA deletions. Single locus displayed high intragroup variation, suggesting cellular heterogeneity within the tissue may be associated to cirDNA release. Our result showed that exposure to IH increases the shedding of cirDNA into circulation, which carries epigenetic modifications that may characterize cell populations within the tumor that preferentially release their DNA upon IH exposure. 6 xenografted mouse samples were analyzed by microarray analysis: Mouse exposed to IH (n=3, XenoIH group) and mouse exposed to room air conditions (n=3, XenoRA group)
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Project description:DEAD-box RNA-binding proteins (RBPs) play a significant role in RNA metabolism to achieve cellular homeostasis, including miRNA biogenesis and transcription. Hypoxia induces stemness cell-like characteristics in cancer cells and promotes malignant progression. Despite the fact that hypoxia can induce the changes in protein and RNA modification, thereby regulating downstream gene expressions, how modifications at different molecular layers interplay with each other are poorly understood. Here we show that hypoxia induces HectH9-mediated K63-linked polyubiquitination of the DEAD-box protein DDX17 as well as reduces N6-methyladenosine (m6A) marks in pri-miRNAs. While m6A potentiates DDX17 binding to pri-miRNAs, decreased m6A modifications of pri-miRNAs and increased polyubiquitination of DDX17 under hypoxia lead to decreased DDX17 binding to pri-miRNAs binding. These events enhance the association of DDX17 with the ubiquitin receptor p300 and lead to a decrease in miRNA biogenesis, especially for miRNAs regulating stemness and stemness-related genes. In addition, polyubiquitinated DDX17 together with p300 upregulates H3K56Ac levels on the stemness and stemness-related genes, resulting in enhancement of tumor initiating ability. Post-transcriptionally, decreased miRNA production, including those targeting stemness genes or stemness-related genes, also facilitates tumor initiation. Together, hypoxia triggers DDX17 poly-ubiquitination, which orchestrates dual mechanisms to increase tumor initiating ability and promote tumor progression.
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