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Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2232-2236. doi: 10.1073/pnas.1814102116. Epub 2019 Jan 23.

Optofluidic real-time cell sorter for longitudinal CTC studies in mouse models of cancer.

Hamza B1,2, Ng SR2,3, Prakadan SM2,4,5,6,7, Delgado FF2,8, Chin CR2, King EM2, Yang LF2,8, Davidson SM2,3, DeGouveia KL2,9, Cermak N2,10, Navia AW2,4,5,6,7, Winter PS2,4,5,6,7, Drake RS2,4,5,6,7, Tammela T2, Li CM2,3, Papagiannakopoulos T2, Gupta AJ2,4,5,6,7, Shaw Bagnall J2,8, Knudsen SM2, Vander Heiden MG2,3,6, Wasserman SC8, Jacks T11,3,6,12, Shalek AK11,4,5,6,7,13,14, Manalis SR11,8,15.

Author information

1
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
2
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
3
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
4
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
5
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
7
Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 02139.
8
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
9
Department of Biomedical Engineering, Wentworth Institute of Technology, Boston, MA 02115.
10
Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
11
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142; tjacks@mit.edu shalek@mit.edu srm@mit.edu.
12
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
13
Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Massachusetts Institute of Technology, Cambridge, MA 02139.
14
Department of Immunology, Massachusetts General Hospital, Boston, MA 02114.
15
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.

Abstract

Circulating tumor cells (CTCs) play a fundamental role in cancer progression. However, in mice, limited blood volume and the rarity of CTCs in the bloodstream preclude longitudinal, in-depth studies of these cells using existing liquid biopsy techniques. Here, we present an optofluidic system that continuously collects fluorescently labeled CTCs from a genetically engineered mouse model (GEMM) for several hours per day over multiple days or weeks. The system is based on a microfluidic cell sorting chip connected serially to an unanesthetized mouse via an implanted arteriovenous shunt. Pneumatically controlled microfluidic valves capture CTCs as they flow through the device, and CTC-depleted blood is returned back to the mouse via the shunt. To demonstrate the utility of our system, we profile CTCs isolated longitudinally from animals over 4 days of treatment with the BET inhibitor JQ1 using single-cell RNA sequencing (scRNA-Seq) and show that our approach eliminates potential biases driven by intermouse heterogeneity that can occur when CTCs are collected across different mice. The CTC isolation and sorting technology presented here provides a research tool to help reveal details of how CTCs evolve over time, allowing studies to credential changes in CTCs as biomarkers of drug response and facilitating future studies to understand the role of CTCs in metastasis.

KEYWORDS:

GEMM; circulating tumor cells; metastasis; microfluidic; single-cell RNA-Seq

PMID:
30674677
PMCID:
PMC6369805
DOI:
10.1073/pnas.1814102116
[Indexed for MEDLINE]
Free PMC Article

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