A combined microfluidic-transcriptomic approach to characterize the extravasation potential of cancer cells
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Simone Bersini1,*, Agnes Miermont2,*, Andrea Pavesi3, Roger Dale Kamm2,4, Jean Paul Thiery3,5, Matteo Moretti1,6,7 and Giulia Adriani2
1Cell and Tissue Engineering Laboratory, Istituto Ortopedico Galeazzi, Milano, Italy
2BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, Singapore
3Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore
4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
5Yong Loo Lin School of Medicine, Department of Biochemistry, National University of Singapore, Singapore
6Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale, Lugano, Switzerland
7Swiss Institute for Regenerative Medicine, Lugano, Switzerland
*These authors contributed equally to this work
Giulia Adriani, email: firstname.lastname@example.org
Matteo Moretti, email: email@example.com
Keywords: microfluidics; microarrays; cancer cell extravasation; tumor microenvironment; organ-specific metastasis
Received: August 01, 2018 Accepted: October 25, 2018 Published: November 16, 2018
The reciprocal interaction between circulating tumor cells (CTCs) and tissue-specific cells is influential for the progression of metastases. In particular, the process of extravasation relies on the complex cross-talk between cancer cells and other cellular players such as the endothelium and the secondary tissue. However, most in vitro studies only focus on one heterotypic cell-cell interaction and often lack of physiological relevance. In this project, we investigated both CTC-endothelium and CTC-secondary site interactions during cancer cell extravasation. We first used a microarray analysis of extravasated MDA-MB-231 breast cancer cells to identify key markers involved in extravasation. Then, we developed a tri-culture microfluidic platform combining cancer cells, endothelium and a bone-mimicking (BMi) microenvironment to assess how organ tropism influences the extravasation potential of cancer cells from different tissues. Through the microarray analyses of extravasated cancer cells we found that extravasation is associated with upregulation of late-metastatic markers along with specific proteases, such as matrix metalloprotease (MMP), a-disintegrin and metalloprotease (ADAM) and a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family members, which are all involved in endothelium glycocalyx shedding. Through the microfluidic extravasation assay, we found that the bone-like microenvironment increased invasion and motility of breast, bladder and ovarian cancer cell (MDA-MB-231, T24 and OVCAR-3). Among the three cell types, ovarian cancer cells presented the lowest migration rate and bladder cancer cells the highest, hence recapitulating their different level of bone tropism observed in vivo. Taken together, our results shed light on the importance of intercellular communication between CTCs and other non-tumor cells essential for promoting cancer cell extravasation.
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