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An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments.

ABSTRACT: During metastasis, cancerous cells leave the primary tumour, pass into the circulatory system, and invade into new tissues. To migrate through the wide variety of environments they encounter, the cells must be able to remodel their cell shape efficiently to squeeze through small gaps in the extracellular matrix or extravasate into the blood stream or lymphatic system. Several studies have shown that the nucleus is the main limiting factor to migration through small gaps (Wolf et al., 2013; Harada et al., 2014; Mak et al., 2013). To understand the physical limits of cancer cell translocation in confined environments, we have fabricated a microfluidic device to study their ability to adapt their nuclear and cellular shape when passing through small gaps. The device is open access for ease of use and enables examination of the effect of different levels of spatial confinement on cell behaviour and morphology simultaneously. The results show that increasing cell confinement decreases the ability of cells to translocate into small gaps and that cells cannot penetrate into the microchannels below a threshold cross-section.

SUBMITTER: Malboubi M

PROVIDER: S-EPMC4567073 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments.

Malboubi Majid M Jayo Asier A Parsons Maddy M Charras Guillaume G

Microelectronic engineering 20150801

During metastasis, cancerous cells leave the primary tumour, pass into the circulatory system, and invade into new tissues. To migrate through the wide variety of environments they encounter, the cells must be able to remodel their cell shape efficiently to squeeze through small gaps in the extracellular matrix or extravasate into the blood stream or lymphatic system. Several studies have shown that the nucleus is the main limiting factor to migration through small gaps (Wolf et al., 2013; Harad ...[more]

PMID: 26412914

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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.

Dataset Information

An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments.

Publications

An open access microfluidic device for the study of the physical limits of cancer cell deformation during migration in confined environments.

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