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Published March 7, 2017 | Erratum + Supplemental Material + Published
Journal Article Open

High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients


Malignant pleural effusion (MPE), the presence of malignant cells in pleural fluid, is often the first sign of many cancers and occurs in patients with metastatic malignancies. Accurate detection of tumor cells in pleural fluid is crucial because the presence of MPE denotes an advanced stage of disease and directs a switch in clinical managements. Cytology, as a traditional diagnostic tool, has limited sensitivity especially when tumor cells are not abundant, and may be confounded by reactive mesothelial cells in the pleural fluid. We describe a highly sensitive approach for rapid detection of metabolically active tumor cells in MPE via exploiting the altered glucose metabolism of tumor cells relative to benign cells. Metabolically active tumor cells with high glucose uptake, as evaluated by a fluorescent glucose analog (2-NBDG), are identified by high-throughput fluorescence screening within a chip containing 200,000 addressable microwells and collected for malignancy confirmation via single-cell sequencing. We demonstrate the utility of this approach through analyzing MPE from a cohort of lung cancer patients. Most candidate tumor cells identified are confirmed to harbor the same driver oncogenes as their primary lesions. In some patients, emergence of secondary mutations that mediate acquired resistance to ongoing targeted therapies is also detected before resistance is manifested in the clinical imaging. The detection scheme can be extended to analyze peripheral blood samples. Our approach may serve as a valuable complement to cytology in MPE diagnosis, helping identify the driver oncogenes and resistance-leading mutations for targeted therapies.

Additional Information

© 2017 National Academy of Sciences. Edited by Chad A. Mirkin, Northwestern University, Evanston, IL, and approved January 31, 2017 (received for review July 25, 2016). Published online before print February 21, 2017. We thank the following agencies and foundations for support: National Natural Science Foundation of China Grants 81373621 (to Q.S.) and 81401880 (to S.L.) and Shanghai Scientific Research Projects Grant 14140902800 (to S.L.), National Key Research and Development Program Grant 2016YFC0900200, NIH Grant 1U54 CA199090-01 (to W.W. and J.R.H.), the Phelps Family Foundation (W.W.), and Shanghai Chest Hospital Grant 2014YZDC10600 (to S.L.). Y.T., Z.W., and Z.L. contributed equally to this work. Author contributions: W.W., S.L., and Q.S. designed research; Y.T., Z.W., J.K., and Y.D. performed research; Z.L., Y.L., and S.L. contributed clinical samples; Y.T., Z.W., W.W., and Q.S. analyzed data; and J.R.H., W.W., and Q.S. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Data deposition: The WES data reported in this paper have been deposited in the ArrayExpress database (accession no. E-MTAB-4948). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612229114/-/DCSupplemental.


Correction for "High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients," by Yin Tang, Zhuo Wang, Ziming Li, Jungwoo Kim, Yuliang Deng, Yan Li, James R. Heath, Wei Wei, Shun Lu, and Qihui Shi, which appeared in issue 10, March 7, 2017, of Proc Natl Acad Sci USA (114:2544–2549; first published February 21, 2017; 10.1073/pnas.1612229114). The authors note that the affiliation for Yin Tang, Zhuo Wang, Yuliang Deng, and Qihui Shi should instead appear as Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. The authors also note that the affiliation for Ziming Li and Shun Lu should instead appear as Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. The corrected author and affiliation lines appear below. The online version has been corrected.

Attached Files

Published - PNAS-2017-Tang-2544-9.pdf

Supplemental Material - pnas.1612229114.sapp.pdf

Supplemental Material - pnas.1612229114.sd05.xlsx

Erratum - PNAS-2017--E2983.pdf


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August 19, 2023
October 20, 2023