Abstract
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.
Highlights
Adult gliomas are the most common cancers of the central nervous system (CNS).[1]
In order to delineate the intratumoral hierarchy of OPCoriginated gliomas, we resorted to a genetic mouse model and performed droplet-based single-cell RNA sequencing.[8]
Together with the findings that no significant change in the total number of oligodendrocyte precursor cells (OPCs)-lineage cells was detected among the three Mosaic Analysis with Double Markers (MADM) models at all developmental time points except for P5 (Figure 4H), we propose that IGF1R deactivation affects mutant and adjacent WT OPCs in opposite ways: it suppresses the overexpansion of mutant OPCs but recovers the number of normal OPCs, like by rebalancing the growth fitness between the two genotypes of OPCs
Summary
Adult gliomas are the most common cancers of the central nervous system (CNS).[1]. Despite many years of efforts, the prognosis of malignant gliomas, the most advanced one, glioblastoma multiforme (GBM), remains dismal. The cell-of-origin can be considered as a rational “normal” reference, as it shares significantly more key features with pretransforming and cancer cells than with irrelevant cell types Following this concept, two studies identified Bone marrow X-linked kinase (BMX) selectively suppressed the self-renewal of human glioma tumor initiating cells (TICs) but not affected either cultured neural stem cells (NSCs) or astrocytes,[2,3] both of. C. Liu School of Brain Science and Brain Medicine NHC and CAMS Key Laboratory of Medical Neurobiology Zhejiang University School of Medicine Hangzhou 310058, China models.[15,16,19,20,21,22] it remains unclear whether all cells in the development hierarchy of glioma respond to IGF1R targeting considering the highly heterogeneous features of GBMs in a native tumor. We addressed these important questions by using genetic autochthonous mouse glioma models, in combination with ex vivo cell culture system as well as patient-derived xenografts (PDX) models
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