Hypoxia stimulates CTC-platelet cluster formation to promote breast cancer metastasis
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ABSTRACT:
PROVIDER: PRJNA1079687 | ENA |
REPOSITORIES: ENA
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Project description:Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTCs). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in BC metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA-seq of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.
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Project description:Single-cell RNA sequencing (scRNA-seq) holds great potential to revolutionize our understanding of cancer biology by discovering biomarkers and biological functions from circulating tumor cells (CTCs). However, the contamination from blood cells is one of the main challenges in CTC studies. Through investigation of recently published studies, we found that several previously reported CTC “biomarkers” were apparently contaminated by blood-derived transcripts such as HBB, HBA1/2, ITGA2B, and LCP1. Through re-analysis of several published CTC and cell line datasets, we revealed that CTC “biomarkers” were not only highly expressed in blood, but showed a high correlation between CTC and blood. We sequenced transcriptome of seven blood components from a healthy donor, finding that the platelet exhibited the highest probability to confound CTC data in terms of expression profiling and correlation analysis. Using CTC spike-in and recovery assay and we showed that the platelet induced artifacts could be reproduced in vitro. Surprisingly, the reproduced artifacts were also highly expressed in the platelet data but not in the other six blood components. We performed SNP calling on recovered CTC simulators, finding cross-contamination of exogenous transcripts. Furthermore, we applied a multiple linear regression model to estimate the platelet confounding index, showing that previously published CTC datasets were confounded with 13%~26% of platelet fractions and 7.9%~17% platelet cloaking judged by fluorescence flow cytometry. We devised a red blood cell lysis based protocol that better removed platelet compared to several platelet inhibitory reagents and kept transcriptomic profile undisturbed in CTC scRNA-seq. This work not only demonstrated the potential blood cell confounding factors in CTC studies, validated them in the past published datasets, and reproduced the artifacts in CTC simulation assay, but also devised an easily applicable method to remove the platelet cloaking, guaranteeing the reliability of CTC scRNA-seq research.
2020-04-18 | GSE135992 | GEO
Project description:MicroRNAs (miRNAs) regulate cell physiology by altering protein expression, but the biology of platelet miRNAs is largely unexplored. We tested whether platelet miRNA levels were associated with platelet reactivity by genome-wide profiling using platelet RNA from 19 healthy subjects. We found that human platelets express 284 miRNAs. Unsupervised hierarchical clustering of miRNA profiles resulted in 2 groups of subjects that appeared to cluster by platelet aggregation phenotypes. Seventy-four miRNAs were differentially expressed (DE) between subjects grouped according to platelet aggregation to epinephrine, a subset of which predicted the platelet reactivity response. Using whole genome mRNA expression data on these same subjects, we computationally generated a high-priority list of miRNA-mRNA pairs in which the DE platelet miRNAs had binding sites in 3'UTRs of DE mRNAs, and the levels were negatively correlated. Three miRNA-mRNA pairs (miR-200b:PRKAR2B, miR-495:KLHL5 and miR-107:CLOCK) were selected from this list and all 3 miRNAs knocked down protein expression from the target mRNA. Reduced activation from platelets lacking PRKAR2B supported these findings. In summary, (1) platelet miRNAs are able to repress expression of platelet proteins, (2) miRNA profiles are associated with and may predict platelet reactivity, and (3) bioinformatic approaches can successfully identify functional miRNAs in platelets. Total RNA from the platelets of 19 donors was harvested and labeled with Hy3. Reference RNA (a pool of all samples) was labeled with Hy5. This submission represents the miRNA expression component of the study.
2011-09-26 | E-GEOD-27917 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) regulate cell physiology by altering protein expression, but the biology of platelet miRNAs is largely unexplored. We tested whether platelet miRNA levels were associated with platelet reactivity by genome-wide profiling using platelet RNA from 19 healthy subjects. We found that human platelets express 284 miRNAs. Unsupervised hierarchical clustering of miRNA profiles resulted in 2 groups of subjects that appeared to cluster by platelet aggregation phenotypes. Seventy-four miRNAs were differentially expressed (DE) between subjects grouped according to platelet aggregation to epinephrine, a subset of which predicted the platelet reactivity response. Using whole genome mRNA expression data on these same subjects, we computationally generated a high-priority list of miRNA-mRNA pairs in which the DE platelet miRNAs had binding sites in 3'UTRs of DE mRNAs, and the levels were negatively correlated. Three miRNA-mRNA pairs (miR-200b:PRKAR2B, miR-495:KLHL5 and miR-107:CLOCK) were selected from this list and all 3 miRNAs knocked down protein expression from the target mRNA. Reduced activation from platelets lacking PRKAR2B supported these findings. In summary, (1) platelet miRNAs are able to repress expression of platelet proteins, (2) miRNA profiles are associated with and may predict platelet reactivity, and (3) bioinformatic approaches can successfully identify functional miRNAs in platelets.
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2020-09-08 | GSE126669 | GEO
Project description:Bacillus thuringiensis strain:CTC Genome sequencing
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Project description:The CTC-iChip microfluidic device [PMID: 23552373 ] enables isolation of rare viable circulating tumor cells (CTCs) directly from whole blood specimens of patients with cancer. Reanalysis of freshly isolated CTC from 31 women with hormone receptor positive metastatic breast cancer.
2023-06-20 | GSE215886 | GEO
Project description:In many patients with solid tumors circulating tumor cells (CTCs), that form metastases, can be identified in peripheral blood. Detection and characterization of CTCs in cancer patients provide a unique opportunity to predict patient survival, select and monitor the efficacy of treatment as well as to gain insights into the cascade of metastatic events. Here, we describe a novel approach to identify CTC-specific molecular markers. Using an integrated platform for immunomagnetic enrichment and immunofluorescent identification of CTCs, blood samples with large numbers of CTCs were identified from patients with colorectal, prostate and breast cancers. Despite enrichment, CTCs are still outnumbered by "nonspecifically" captured leukocytes. In order to determine gene expression profile for CTCs, "background" gene expression signature of white blood cells must be taken into account. To this end, following enrichment for CTCs, RNA was also extracted from the remaining CTC-depleted blood samples. The following samples were used to generate the global expression profiles for CTCs:<br><br> 1a) SAMPLE170711SUB735: CTC-enriched blood sample from a patient with breast cancer). 3700 CTCs were identified per 7.5 ml of peripheral blood in this patient.<br> 1b) SAMPLE170712SUB735: Corresponding CTC-depleted blood sample for the above patient with breast cancer.<br> 2a) SAMPLE170829SUB750: CTC-enriched blood sample from a patient with prostate cancer. 647 CTCs were identified per 7.5 ml of peripheral blood in this patient.<br> 2b) SAMPLE170830SUB750: Corresponding CTC-depleted blood sample for the above patient with prostate cancer.<br> 3a) SAMPLE170831SUB751: CTC-enriched sample from a patient with colorectal cancer. 180 CTCs were identified per 7.5 ml of peripheral blood in this patient.<br> 3b) SAMPLE170832SUB751: Corresponding CTC-depleted blood sample for the above patient with colorectal cancer.
2005-06-30 | E-MEXP-136 | biostudies-arrayexpress
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