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Characterizing breast cancer lung metastatic lesions in host environments with or without NK cells by RNA-seq

ABSTRACT: We demonstrated that natural killer (NK) cells selectively suppress single circulating tumor cells (CTCs) and monoclonal metastasis compared to multicellular CTC clusters and polyclonal metastasis. To better understand how NK cells influence overall metastatic evolution, we generated spontaneous AT3 breast cancer lung metastasis in immunodeficient Rag2-/-IL2rg-/- mice, and treated mice with or without adoptive transfer of NK cells. RNA-seq on individual laser-capture microdissected lesions confirmed the infiltration of NK cells. The expression of epithelial-to-mesenchymal transition (EMT) genes strongly correlated with expression of genes indicating NK cell activation, consistent with experimental data from our lab and others.

ORGANISM(S): Mus musculus

PROVIDER: GSE144713 | GEO | 2020/04/16

REPOSITORIES: GEO

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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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Single-cell metabolic fingerprints discover a cluster of circulating tumor cells with distinct metastatic potential

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2023-08-21 | MTBLS5028 | MetaboLights

Transcriptomic analysis of femoral diaphysis and primary osteoprogenitor cells cultures from mouse strains with SHIP1 deficiency and controls

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2024-02-21 | E-MTAB-13164 | biostudies-arrayexpress

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Project description:Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTCs) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from breast cancer patients are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. We used ATAC-seq to assay chromatin accessibility in parental CTC and CTC-derived metastatic cells. Genome-wide sequencing analyses of metastatic variants identified novel chromatin accessibility domains predicting organ-specific metastasis identified from CTCs and facilitate the development of potential therapies targeting metastatis initiating cells in circulation.

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2019-06-02 | GSE82198 | GEO

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Project description:Comprehensive analyses of cancer genomes in clinical settings promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the inaccessibility of adequate metastatic tissue for accurate genomic analysis in prostate and other cancers. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple technical hurdles. Here, we report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of over 99.995% of the territory accessible in bulk exome sequencing is possible in CTCs. We validated our sequencing process in two prostate cancer patients including one for whom we compared CTC-derived mutations to mutations found in a lymph node metastasis and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

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