title: Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells.
abstract: Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, 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, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Health Sciences, University of Genoa, 16126 Genoa, Italy.
authors.forename: Matteo
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authors.lastname: Ligorio
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Vincent Jordan
authors.affiliation: Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ajay M
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authors.lastname: Shah
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Radiation Oncology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kristina
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authors.lastname: Xega
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jordan C
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authors.lastname: Ciciliano
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Huili
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authors.lastname: Zhu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Olivia C
authors.initials: OC
authors.lastname: MacKenzie
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Trautwein
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kshitij S
authors.initials: KS
authors.lastname: Arora
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Haley L
authors.initials: HL
authors.lastname: Ellis
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Qu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, 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, Boston, MA 02114, USA; Department of Surgery, 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, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D015676:Osteonectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; C509134:IGFBP5-interacting protein, human; D015676:Osteonectin; D034741:RNA, Small Interfering; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase