de Pablo, C. | Search bioRxiv

bioRxiv2023

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

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.

cancer biology↗

bioRxiv2020

Insulin signaling mediates neurodegeneration in glioma

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how the glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue the synapse loss and to delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies. Significance StatementGlioblastoma (GB) is the most aggressive type of brain tumour and currently there is no cure or effective treatment. Patients course with neurological decay and previous data in animal models indicate that GB cause a neurodegenerative process. We describe here a molecule named ImpL2 that is produced by GB cells and impact on neighbouring neurons. ImpL2 is an antagonist of the insulin pathway and signaling reduction in neurons causes mitochondrial defects and synapse loss. These mechanisms underlying GB-induced neurodegeneration plays a central role in the premature death caused by this tumour. Restoration of insulin signaling in neurons prevents tumour progression and rescues the lethality caused by GB in Drosophila models.

neuroscience↗