Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish

The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human glioma-genesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.

Automated summary

The molecular pathogenesis of glioblastoma is critical for human gliomagenesis, with RTK/Ras/PI3K, RB, and TP53 pathways playing key roles. Using transgenic zebrafish with single or multiple gene deletions, researchers induced gliomagenesis and found that nf1 mutation alone had low efficiency, but combined deletions of nf1;tp53 and rb1;tp53 resulted in higher tumor incidences with advanced histology. Bioinformatics analysis revealed alterations in critical pathways like RTK/Ras/PI3K, cell cycle, and focal adhesion, highlighting their importance in gliomagenesis initiation and development. Tumors in zebrafish models showed significant similarities to human gliomas, and temozolomide treatment effectively suppressed gliomagenesis, mimicking responses seen in clinical glioma treatment. This study provides a potential tool for genetically studying gliomagenesis and screening targeted anti-tumor compounds for glioma treatment.