Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 3, Pages 851-856Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320611111
Keywords
cancer; glioblastoma; clonal heterogeneity; genomic analysis; functional analysis
Categories
Funding
- Ontario Institute for Cancer Research
- Government of Ontario
- Canadian Institutes for Health Research (CIHR)
- Genome Canada
- Canadian Cancer Society
- Hospital for Sick Children Foundation
- Jessica's Footprint Foundation
- Hopeful Minds Foundation
- National Resource for Network Biology (US National Institutes of Health) [P41 GM103504]
- CIHR
- Toronto Western Hospital Brain Tumor Bank
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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, naive 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.
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