micromanipulation-circulating-tumor-cells-for-downstream-molecular

Micromanipulation of Circulating Tumor Cells for Downstream Molecular Analysis and Metastatic Potential Assessment

Blood-borne metastasis accounts for&#160;most cancer-related deaths and involves circulating tumor cells (CTCs) that are successful in establishing new ...

University of Basel and University Hospital Basel

The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive.

Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer.

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na/K ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.

Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs). The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.

Article	Year
Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer. Breast cancer research : BCR\| PubMed ID: 30458879	2018
Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell\| PubMed ID: 30633912	2019
Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature\| PubMed ID: 30728496	2019

Nicola Aceto

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