title: Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks inex vivoculture.
abstract: Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.
  
  
  
  Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.
  
  
  
  Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, bothin vitroandin vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.
  
  
  
  Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.
  
  
  
  ClinicalTrial.gov NCT01577511.
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Grillet
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Bayet
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Villeronce
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Zappia
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Ebba Louise
authors.initials: EL
authors.lastname: Lagerqvist
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, U1068 Inserm, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.|Center for Translational Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Kym
authors.initials: K
authors.lastname: Pham
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Molck
authors.affiliation: Service d'anatomopathologie, CHU Carémeau, Nîmes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rolland
authors.affiliation: Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Bourgaux
authors.affiliation: Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Prudhomme
authors.affiliation: Service de Chirurgie Digestive, CHU Carémeau, Nîmes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Laboratoire de Biochimie, CHU Carémeau, Nîmes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bravo
authors.affiliation: Laboratoire de Biochimie, CHU Carémeau, Nîmes, France.
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Boyer
authors.affiliation: Plateforme MPCC-SIRIC Montpellier Cancer, IRCM, Montpellier, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Canterel-Thouennon
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Graham Roy
authors.initials: GR
authors.lastname: Taylor
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Hsu
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
authors.affiliation: Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.|Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France.|Université de Montpellier, UMR5203, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pannequin
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D002454:Cell Differentiation; D000066673:Cell Self Renewal; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000235:genetics; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary; D051379:Mice; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000502:physiology; D010641:Phenotype; D061251:Primary Cell Culture; D012334:RNA, Neoplasm / Q000032:analysis*; D050697:Retinal Dehydrogenase; D017423:Sequence Analysis, RNA; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D012334:RNA, Neoplasm; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D018819:Dipeptidyl Peptidase 4
keywords: COLORECTAL CANCER; DRUG TOXICITY; LIVER METASTASES