Open AccessOncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting
Author(s) -
Tian Anhao,
Kang Bo,
Li Baizhou,
Qiu Biying,
Jiang Wenhong,
Shao Fangjie,
Gao Qingqing,
Liu Rui,
Cai Chengwei,
Jing Rui,
Wang Wei,
Chen Pengxiang,
Liang Qinghui,
Bao Lili,
Man Jianghong,
Wang Yan,
Shi Yu,
Li Jin,
Yang Minmin,
Wang Lisha,
Zhang Jianmin,
Hippenmeyer Simon,
Zhu Junming,
Bian Xiuwu,
Wang YingJie,
Liu Chong
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202001724
Subject(s) - insulin like growth factor 1 receptor , glioma , biology , cancer cell , cancer research , neural stem cell , cancer stem cell , cancer , stem cell , microbiology and biotechnology , neuroscience , growth factor , receptor , genetics
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.