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Tumor-derived circulating endothelial cell clusters in colorectal cancer

ABSTRACT: Circulating tumor cells (CTCs) are the subject of several translational studies and clinical trials because their examination could offer an insight into tumor progression and clinical outcomes. Circulating tumor microemboli (CTM) are clusters of CTCs that have been described as malignant entities for over 50 years, although a comprehensive characterization of these cells is still lacking. Contrary to current consensus, we demonstrate that CTM isolated from colorectal cancer patients are not cancerous, but represent a discrete population of tumor-derived endothelial cells. CTM express epithelial and mesenchymal markers that are consistent with previous reports on circulating tumor cell phenotyping. However, they do not mirror the genetic variations of matching tumors. Transcriptome analysis of single-CTM reveals that these structures exhibit an endothelial phenotype, with further results supporting a tumor-derived endothelial lineage. CTM are widespread in blood sampled from preoperative cancer patients but not in healthy donors, suggesting CTM count as a potential biomarker of interest for colorectal cancer. CTM should not be confused with bona fide circulating epithelial tumor cells. The characterization of tumor derived endothelial cell clusters (TECCs) is likely of high diagnostic value, and may provide direct information about the underlying tumor vasculature at the time of diagnosis, during treatment and the course of the disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74369 | GEO | 2016/06/20

SECONDARY ACCESSION(S): PRJNA300264

REPOSITORIES: GEO

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Project description:Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tu-mor cells, CTCs) either alone or Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tu-mor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tis-sue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on com-panion cells in clusters.as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tis-sue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on com-panion cells in clusters.

Project description:Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Highly parallel architecture of the chip allows deterministic screening of clinically relevant volumes of blood samples at slow, and hence, non-damaging flow rates. Using the Cluster-Chip, we identify CTC-clusters in 30-40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as being tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis. We used the Cluster-Chip to capture CTC-clusters from the blood of a breast cancer patient with high CTC counts, released CTC-clusters in solution, stained them with TexasRed-conjugated antibodies against the leukocyte cell surface markers CD45, CD14 and CD16, and then isolated intact CTC-clusters individually using a micromanipulator. From a single time point, we retrieved 15 CTC-clusters, and each of those clusters was individually subjected to RNA-sequencing analysis using a next generation platform (SOLiD 5500). In addition, two leukocytes were isolated from the blood of a healthy donor were individually subjected to RNA-sequencing analysis using the same platform.

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Tumor-derived circulating endothelial cell clusters in colorectal cancer

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