title: Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells.
abstract: Circulating tumor cells (CTCs) are shed into the bloodstream from primary and metastatic tumor deposits. Their isolation and analysis hold great promise for the early detection of invasive cancer and the management of advanced disease, but technological hurdles have limited their broad clinical utility. We describe an inertial focusing-enhanced microfluidic CTC capture platform, termed "CTC-iChip," that is capable of sorting rare CTCs from whole blood at 10(7) cells/s. Most importantly, the iChip is capable of isolating CTCs using strategies that are either dependent or independent of tumor membrane epitopes, and thus applicable to virtually all cancers. We specifically demonstrate the use of the iChip in an expanded set of both epithelial and nonepithelial cancers including lung, prostate, pancreas, breast, and melanoma. The sorting of CTCs as unfixed cells in solution allows for the application of high-quality clinically standardized morphological and immunohistochemical analyses, as well as RNA-based single-cell molecular characterization. The combination of an unbiased, broadly applicable, high-throughput, and automatable rare cell sorting technology with generally accepted molecular assays and cytology standards will enable the integration of CTC-based diagnostics into the clinical management of cancer.
authors.affiliation: Massachusetts General Hospital Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Ozkumur
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Jordan C
authors.initials: JC
authors.lastname: Ciciliano
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Emmink
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.forename: Elena
authors.initials: E
authors.lastname: Brachtel
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Pin-i
authors.initials: PI
authors.lastname: Chen
authors.forename: Bailey
authors.initials: B
authors.lastname: Morgan
authors.forename: Julie
authors.initials: J
authors.lastname: Trautwein
authors.forename: Anya
authors.initials: A
authors.lastname: Kimura
authors.forename: Sudarshana
authors.initials: S
authors.lastname: Sengupta
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stott
authors.forename: Nezihi Murat
authors.initials: NM
authors.lastname: Karabacak
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Barber
authors.forename: John R
authors.initials: JR
authors.lastname: Walsh
authors.forename: Kyle
authors.initials: K
authors.lastname: Smith
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Spuhler
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Aditya
authors.initials: A
authors.lastname: Bardia
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapur
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods*; D048430:Cell Shape; D048429:Cell Size; D005260:Female; D006801:Humans; D060328:Magnetic Phenomena; D008297:Male; D044085:Microfluidics / Q000379:methods*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D012334:RNA, Neoplasm / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D012334:RNA, Neoplasm
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3970-5
references.pmid: 19234122
references.citation: Cell. 2011 Apr 1;145(1):19-24
references.pmid: 21458664
references.citation: Cytometry. 1990;11(2):231-8
references.pmid: 1690625
references.citation: Nature. 2007 Dec 20;450(7173):1235-9
references.pmid: 18097410
references.citation: Biotechnol Bioeng. 2009 Feb 1;102(2):521-34
references.pmid: 18726961
references.citation: Genes Dev. 2009 Aug 1;23(15):1737-42
references.pmid: 19651985
references.citation: Angew Chem Int Ed Engl. 2011 Mar 21;50(13):3084-8
references.pmid: 21374764
references.citation: Biomicrofluidics. 2011 Mar 30;5:13413
references.pmid: 21526007
references.citation: Science. 2004 May 14;304(5673):987-90
references.pmid: 15143275
references.citation: Prenat Diagn. 2008 Oct;28(10):892-9
references.pmid: 18821715
references.citation: Breast Cancer Res. 2008;10(4):R69
references.pmid: 18687126
references.citation: J Cell Biol. 2011 Feb 7;192(3):373-82
references.pmid: 21300848
references.citation: Science. 2013 Feb 1;339(6119):580-4
references.pmid: 23372014
references.citation: Sci Transl Med. 2012 Jul 4;4(141):141ps13
references.pmid: 22764205
references.citation: N Engl J Med. 2008 Jul 24;359(4):366-77
references.pmid: 18596266
references.citation: Sci Transl Med. 2012 Jul 4;4(141):141ra92
references.pmid: 22764208
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Clin Cancer Res. 2004 Oct 15;10(20):6897-904
references.pmid: 15501967
references.citation: Exp Hematol. 2004 Oct;32(10):891-904
references.pmid: 15504544
references.citation: Cancer Discov. 2012 Nov;2(11):995-1003
references.pmid: 23093251
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18892-7
references.pmid: 18025477
references.citation: J Natl Cancer Inst. 2009 Jan 7;101(1):61-6
references.pmid: 19116383
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10501-4
references.pmid: 15249663
references.citation: Sci Transl Med. 2010 Mar 31;2(25):25ra23
references.pmid: 20424012
references.citation: Anal Chem. 2011 Mar 15;83(6):2301-9
references.pmid: 21319808
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18392-7
references.pmid: 20930119
references.citation: Nat Rev Cancer. 2008 May;8(5):329-40
references.pmid: 18404148
references.citation: Phys Biol. 2012 Feb;9(1):016003
references.pmid: 22306768
references.citation: J Oncol. 2010;2010:617421
references.pmid: 20016752