Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting

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.

In Vivo Clonal Analysis Reveals Development Heterogeneity of Oligodendrocyte Precursor Cells Derived from Distinct Germinal Zones

“…We have previously used this system to examine the division pattern of OPCs after acquiring glioma‐relevant mutations. [ 15 , 51 ] Therefore, we used tamoxifen‐inducible NG2‐Cre ERT to induce mitotic recombination directly in OPCs at P3 and examine the clonality of labeled cells. We confirmed that only OPC‐lineage cells could be labeled in the system and that the labeling was fully dependent on the presence of tamoxifen (data not shown).…”

“…Knockout of NF1 in OPCs or neural progenitors resulted in dramatic overexpansion of OPCs at the population level. [ 54 , 55 , 56 , 57 ] Therefore, we examined whether NF1 deficiency could prevent the loss of ventrally derived OPCs during development.…”

A genome-wide library of MADM mice for single-cell genetic mosaic analysis

“…One clinically relevant application of MADM is the tracing of tumor growth upon sparse or clonal ablation of tumor suppressor genes and/or to assay for the effects of therapeutic agents. As such, MADM has been used for the analysis of tumor formation and the delineation of cancer cell of origin at the single-cell level in the brain and distinct organs (Muzumdar et al, 2007(Muzumdar et al, , 2016Liu et al, 2011;Gonzalez et al, 2018;Tian et al, 2020;Yao et al, 2020).…”

Interferon-Beta Inhibits Human Glioma Stem Cells Rather Than Neural Stem Cells via Cell Cycle and Immune Signaling

“…Our results indicated that IFN-β affected hGSCs rather than hNSCs. hNSCs are considered to be the most likely initiation cells of malignant glioma [17,25,26]. On the other hand, hNSCs have been considered efficient vehicles for the delivery of anti-cancer agents to tumor sites during therapeutic applications [39,40].…”

“…During malignant glioma treatment, at least two aspects of NSCs are related to GSCs. On the one hand, mutated NSCs are considered to be the initiation cells of glioma [17,25,26]. On the other hand, normal NSCs are considered to have the ability to move towards GSCs, and can be used as carriers for the treatment of gliomas [27,28].…”