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

Tang, Yin and Wang, Zhuo and Li, Ziming and Kim, Jungwoo and Deng, Yuliang and Li, Yan and Heath, James R. and Wei, Wei and Lu, Shun and Shi, Qihui (2017) High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients. Proceedings of the National Academy of Sciences of the United States of America, 114 (10). pp. 2544-2549. ISSN 0027-8424. PMCID PMC5347549. https://resolver.caltech.edu/CaltechAUTHORS:20170221-160921243

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1612229114 DOIArticle
http://www.pnas.org/content/114/10/2544PublisherArticle
http://www.pnas.org/content/114/10/2544?tab=dsPublisherSupporting Information
http://dx.doi.org/10.1073/pnas.1703650114 ErrataCorrection
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347549/PubMed CentralArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389322/PubMed CentralCorrection
ORCID:
AuthorORCID
Kim, Jungwoo0000-0002-5215-2044
Heath, James R.0000-0001-5356-4385
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.
Errata: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.
Funders:
Funding AgencyGrant Number
National Natural Science Foundation of China81373621
National Natural Science Foundation of China81401880
Shanghai Scientific Research Projects14140902800
National Key Research and Development Program2016YFC0900200
NIH1U54CA199090-01
Phelps Family FoundationUNSPECIFIED
Shanghai Chest Hospital2014YZDC10600
Issue or Number:10
PubMed Central ID:PMC5347549
Record Number:CaltechAUTHORS:20170221-160921243
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170221-160921243
Official Citation:Yin Tang, Zhuo Wang, Ziming Li, Jungwoo Kim, Yuliang Deng, Yan Li, James R. Heath, Wei Wei, Shun Lu, and Qihui Shi High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients PNAS 2017 114 (10) 2544-2549; published ahead of print February 21, 2017, doi:10.1073/pnas.1612229114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74441
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:22 Feb 2017 15:54
Last Modified:03 Oct 2019 16:38

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