Journal
ADVANCED SCIENCE
Volume 7, Issue 21, Pages -Publisher
WILEY
DOI: 10.1002/advs.202001724
Keywords
cancer cell of origin; glioma; IGF1R; lineage tracing; mosaic analysis with double markers (MADM); neural stem cells (NSCs); oligodendrocyte precursor cells (OPCs)
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Funding
- National Key Research and Development Program of China, Stem Cell and Translational Research [2016YFA0101201, 2016YFA0100303]
- National Natural Science Foundation of China [81673035, 81972915, 81472722]
- Science Foundation for Distinguished Young Scientists of Zhejiang Province [LR17H160001]
- Fundamental Research Funds for the Central Universities [2016QNA7023, 2017QNA7028]
- Thousand Talent Program for Young Outstanding Scientists, China
- IST Austria institutional funds
- European Research Council (ERC) under the European Union [725780 LinPro]
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Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells-of-origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin-like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new-generation brain-penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.
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