title: Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity.
abstract: Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Mona
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Donnelly Centre, University of Toronto, Toronto, ON, Canada M5S 3E1 Canada;
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Lan
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Renee
authors.initials: R
authors.lastname: Head
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
authors.forename: Michelle
authors.initials: M
authors.lastname: Kushida
authors.affiliation: Department of Transformative Pathology at the Ontario Institute for Cancer Research, Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3;
authors.forename: Jane
authors.initials: J
authors.lastname: Bayani
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada M5S 3G5;
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Pressey
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada M5G 1L7;
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Ontario College of Art and Design, Toronto, ON, Canada M5T 1W1;
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.affiliation: Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8;
authors.forename: Michael
authors.initials: M
authors.lastname: Cusimano
authors.affiliation: Department of Pathology, Queen's University, Kingston, ON, Canada K7L 3N6;
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada M5G 1L7;
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada M5T 2S8; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada M5S 3G5;
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Woodin
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Donnelly Centre, University of Toronto, Toronto, ON, Canada M5S 3E1 Canada; gary.bader@utoronto.ca peter.dirks@sickkids.ca.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8 gary.bader@utoronto.ca peter.dirks@sickkids.ca.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D006801:Humans; D059010:Single-Cell Analysis; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D000077204:Temozolomide
keywords: cancer; clonal heterogeneity; functional analysis; genomic analysis; glioblastoma