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Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [RNA-Seq]

ABSTRACT: Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [RNA-Seq]

PROVIDER: PRJNA1180443 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31179068.fastq.gz	Fastqsanger.gz
	SRR31179069.fastq.gz	Fastqsanger.gz
	SRR31179070.fastq.gz	Fastqsanger.gz
	SRR31179071.fastq.gz	Fastqsanger.gz
	SRR31179072.fastq.gz	Fastqsanger.gz

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Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [RNA-Seq]

Project description:Melanoma brain metastasis (MBM) is linked to dismal prognosis, low overall survival, and is detected in up to 80% of patients at autopsy. Circulating tumor cells (CTCs) are the smallest functional units of cancer and precursors of fatal metastasis. We previously employed an unbiased multilevel approach to discover a unique ribosomal protein large/small subunits (RPL/RPS) CTC gene signature associated with MBM. Here, we hypothesized that CTC-driven MBM secondary metastasis (?metastasis of metastasis? per clinical scenarios), has targeted organ specificity for liver. We injected parallel cohorts of immunodeficient and newly-developed humanized NBSGW (HuNBSGW) mice with cells from CTC-derived MBM to identify secondary metastatic patterns. We found the presence of a melanoma brain-liver metastasis axis in humanized NBSGW mice. Further, RNA-Seq analyses of tissues showed a significant upregulation of the RPL/RPS CTC gene signature linked to metastatic spread to liver. Additional RNA-Seq of CTCs from HuNBSGW blood revealed extensive CTC clustering with human B cells in these mice. CTC:B cell clusters were also upregulated in blood of primary melanoma patients, and maintained either in CTC-driven MBM or MBM CTC-derived cells promoting liver metastasis. CTC-generated tumor tissues were interrogated at single-cell gene and protein expression levels (10x Genomics Xenium and HALO spatial biology platforms, respectively). Collectively, our findings suggest that heterotypic CTC:B cell interactions can be critical at multiple stages of metastasis. This study provides important insights for relevance of pro-metastatic CTC:B cell clusters extending from primary metastatic disease, and identifies new targets for therapies of clinical metastasis to improve patient care.

2025-01-14 | GSE280739 | GEO

Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [Xenium]

Project description:Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [Xenium]

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Upregulation of the MBM CTC Signature and CTC:B Cell Clusters Associate with Secondary Liver Metastasis: a Melanoma Brain-Liver Metastasis Axis [Xenium]

Project description:CTC-generated tumor tissues were interrogated at single-cell gene and protein expression levels using 10x Genomics Xenium

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A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain-Liver Metastasis Axis.

Project description:SignificanceThis study provides important insights into the relevance of prometastatic CTC:B-cell clusters in melanoma progression, extends the importance of the CTC RPL/RPS gene signature beyond primary metastasis/melanoma brain metastasis driving targeted organ specificity for liver metastasis ("metastasis of metastasis"), and identifies new targets for clinical melanoma metastasis therapies.

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Circulating Tumor Cell Clusters are Oligoclonal Precursors of Breast Cancer Metastasis

Project description:Clusters of circulating tumor cells (CTC-clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Here, we first use mouse models to demonstrate that breast cancer cells injected intravascularly as clusters are more prone to survive and colonize the lungs than single cells. Primary mammary tumors comprised of tagged cells give rise to oligoclonal CTC-clusters, with 50-fold increased metastatic potential, compared with single CTCs. Using intravital imaging and in vivo flow cytometry, CTC-clusters are visualized in the tumor circulation, and they demonstrate rapid clearance in peripheral vessels. In patients with breast cancer, presence of CTC-clusters is correlated with decreased progression-free survival. RNA sequencing identifies the cell junction protein plakoglobin as most differentially expressed between clusters and single human breast CTCs. Expression of plakoglobin is required for efficient CTC-cluster formation and breast cancer metastasis in mice, while its expression is associated with diminished metastasis-free survival in breast cancer patients. Together, these observations suggest that plakoglobin-enriched primary tumor cells break off into the vasculature as CTC-clusters, with greatly enhanced metastasis propensity. RNA-seq from 29 samples (15 pools of single CTCs and 14 CTC-clusters) isolated from 10 breast cancer patients

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Circulating Tumor Cell Clusters are Oligoclonal Precursors of Breast Cancer Metastasis

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mRNA expression profile in the liver after overexpressed tsRNA-Glu-CTC oligos in C57BL/6 mice with mRNA-seq method

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