title: Isolation and molecular characterization of circulating melanoma cells.
abstract: Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs) have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice and rapidly declined after B-RAF inhibitor treatment. CTCs were shed early from localized tumors, and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant metastases. The large number of CTCs in melanoma-bearing mice enabled a comparison of RNA-sequencing profiles with matched primary tumors. A mouse melanoma CTC-derived signature correlated with invasiveness and cellular motility in human melanoma. CTCs were detected in smaller numbers in patients with metastatic melanoma and declined with successful B-RAF-targeted therapy. Together, the capture and molecular characterization of CTCs provide insight into the hematogenous spread of melanoma.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Devarati
authors.initials: D
authors.lastname: Mitra
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Anya M
authors.initials: AM
authors.lastname: Kimura
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stott
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Center for Engineering in Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013629:Tamoxifen / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase
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