Abstract
Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.
Highlights
Malignant gliomas (MG) are central nervous system tumors of glial origin characterized by molecular heterogeneity and a poor prognosis
Given the significant role of cluster differentiation (CD) genes in immune modulation, and the lack of studies evaluating the expression of these genes in canine glioma, we further expanded our analysis to determine the CD genes differentially expressed in canine ODG
Our results demonstrated that 21 CD genes are differentially expressed in canine ODG compared to normal brains and among these 21 genes, 16 were found to be significantly altered with log2-fold change >2.0 (Figure 1C)
Summary
Malignant gliomas (MG) are central nervous system tumors of glial origin characterized by molecular heterogeneity and a poor prognosis. One of the factors contributing to this lack of translational benefit is the need for a pre-clinical glioma model capable of more accurately predicting the efficacy of novel anti-glioma therapies in human patients [2]. Recent studies have shown that the spontaneous, immunocompetent canine model of glioma may be a solution to this problem given its anatomical, physiological, and molecular similarity to human glioma [2,3,4]. In addition to their biological similarities, human and canine gliomas have demonstrated similar therapeutic responses to chemotherapy, conventional radiotherapy, and stereotactic radiosurgery [3, 5]
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