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Harnessing Small Molecules for Revealing Vulnerabilities in Circulating Tumor Cells.

ABSTRACT: Breast cancer is among the most commonly diagnosed cancers, accounting for 685,000 fatalities in 2020 worldwide. High mortality rate is associated with the development of metastases, a complex process involving the spread of cancer cells from the primary tumor site to secondary organs. At present, treating patients with metastatic disease is challenging, and this still represent an unmet medical need. As clinically-relevant models, circulating tumor cell (CTC)-derived models can serve as a drug screen platforms that enable drug susceptibility testing and discovery of novel compounds with anti-cancer progression activity. Here, by employing a combination of CTC-based drug screening platform, in vivo models of metastatic breast cancer, RNA sequencing, and in vitro cell assays, we identified new agents for the reduction of tumor growth and lung colonization in breast cancer. Furthermore, our transcriptomic data delineate the metastasis-relevant signaling pathways affected by these treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251771 | GEO | 2026/02/18

REPOSITORIES: GEO

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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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Harnessing Small Molecules for Revealing Vulnerabilities in Circulating Tumor Cells.

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