Novel genetic model of pediatric Diffuse Intrinsic Pontine Glioma in Drosophila melanogaster

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric type of brain tumor that grows in the bm and originated from glial cells. Its location and infiltrative nature impede surgical resection and make the treatment difficult and low effective. In consequence, affected children have a short life expectancy of 12 months. The most frequent mutation is a substitution of lysine to methionine at residue 27 of histone H3 (H3K27M). Secondary mutations in additional genes, including Myc, are required for the malignancy of glial cells. The lack of studies and tumor aggressiveness make it necessary to generate new experimental models that reproduce the fundamental aspects of the disease and allow to expand the knowledge about DIPG. Drosophila melanogaster presents advantages as an experimental model and stands out for its genetic tools, easy handling, and great genetic and cellular homology with humans. Drosophila has contributed to the investigation of different diseases, including glioblastoma (GB) and neurodegenerative diseases as Alzheime[r]s or Parkinso[n]s. Here we present a new genetic model of DIPG generated in Drosophila melanogaster. It is based on the overexpression of H3K27 and Myc in glial cells that produce an increase in the number of glial cells in the ventral nerve cord and the expansion of glial membranes in early developmental stages. However, this novel DIPG model does not produce tumoral features in adult brains, in line with the pediatric nature of this disease. We have evaluated the activation of different signaling pathways active in other glial tumors, in this model of DIPG. The results show that, unlike GB, JNK pathway is not upregulated in DIPG, and it is not determinant for the progression of DIPG. Besides, glial cells in the DIPG model accumulate MMP1 and MMP2 and increase the accumulation of Liprin-{gamma}, previously associated to the formation of synaptic structures in GB cells. The results show that DIPG is a unique entity that differs from other high-grade gliomas such as GB and will require of a different therapeutic approach.