Childhood cancers are truly devastating diseases; they cause major loss of young lives due to the distinct lack of treatment options stemming from the limited access to tumor tissues. Hopefully, a promising new study published in Science will change this.
Researchers from the laboratory Viviane Tabar at the Memorial Sloan-Kettering Cancer Center, New York, USA have described the successful creation of a human embryonic stem cell (hESC)-based model of an aggressive childhood brain tumor. This has opened up clinical pathways to treat this tumor type, and also highlights the importance of a mutation in a core histone protein in the development and aggressivity of this cancer.
Previous assessment of diffuse intrinsic pontine gliomas (DIPGs) identified an important interaction between two well-known oncogenic events (p53 mutation and PDGFRA amplification) and a mutation in histone H3.3 at the lysine 27 position, whose methylation leads to the repression of gene transcription.
With this knowledge, the group developed a model system whereby hESC-derived neural progenitor cells (NPCs) expressed constitutively active PDGFRA, a small hairpin RNA (shRNA) against p53, and the K27M-mutant form of histone H3.3 to create P5K-NPCs.
Encouragingly, the group demonstrated that the histone mutation synergized with the other pro-oncogenic changes to specifically induce hallmark tumorigenic changes in NPCs in vitro, making them similar to DIPG cells.
Analysis of this model system revealed:
- an altered gene expression profile which suggested mutant histone H3.3 encourages NPCs to revert to a stem like-state
- alterations in histone lysine methylation patterns at key regulatory genes (assessed by ChIP-Seq)
- tumor formation and spread similar to DIPG upon injection into brainstem of immunocompromised mice.
The successful recapitulation of the DIPG tumor phenotype encouraged the authors to use this model to screen for small molecule inhibitors to combat tumorigenic spread. Amazingly, they identified MI-2, an inhibitor of Menin (trithorax family histone methyltransferase complex member), showing it reduced the tumorigenic capabilities of the P5K-NPCs in vitro and in vivo, and also displayed some anti-tumor activity on a primary cell culture derived from a human DIPG patient.
This incredible research combines stem-cell modeling, tumorigenic profiling, and small molecule screening to greatly enhance our knowledge of this highly aggressive childhood tumor type and widen our therapeutic treatment options.
Read this amazing cross-disciplinary article here: Funato et al, Science, 2014.