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Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):851-6. doi: 10.1073/pnas.1320611111. Epub 2015 Jan 5.

Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity.

Author information

1
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;
2
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Donnelly Centre, University of Toronto, Toronto, ON, Canada M5S 3E1 Canada;
3
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;
4
Department of Transformative Pathology at the Ontario Institute for Cancer Research, Ontario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3;
5
Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada M5S 3G5;
6
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;
7
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;
8
Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8;
9
Department of Pathology, Queen's University, Kingston, ON, Canada K7L 3N6;
10
Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada M5T 2S8; and.
11
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.
12
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.

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.

KEYWORDS:

cancer; clonal heterogeneity; functional analysis; genomic analysis; glioblastoma

PMID:
25561528
PMCID:
PMC4311802
DOI:
10.1073/pnas.1320611111
[Indexed for MEDLINE]
Free PMC Article

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