Fig. 4: Non-genomic contributions to diffuse midline glioma growth and progression.

Diffuse midline gliomas (DMG) are vastly complex tumors localized in the midline structures of the brain. At diagnosis (primary tumor) DMG harbor numerous driver mutations, (highlighted by tumor cells of varying color), that contribute to drive the evolution of the cancer. Surrounding cells and structures of the midline of the brain such as blood vessels, neurons, astrocytes, microglia, and oligodendrocytes contribute to the gliomagenesis of DMG, whether through direct physical connections or by more indirect mechanisms, such as electrical signals (yellow lightening blots) between glioma and normal cells or the contribution of growth hormones, NGF, VEGF, TGF-β, and prolactin, or even, endogenous factors, such as hypoxia, dopamine, insulin, catecholamines. The extracellular cues drive posttranslational modifications (PTMs) that influence the activity of oncoproteins that contribute to the aggressive nature of the disease. It is likely that exogenous factors, such as radiotherapy (radioactive symbol) and corticosteroids (dexamethasone), also contribute to the disease, the impact on tumor growth and treatment resistance yet to be fully understood. The diffuse and infiltrative growth of this cancer also leads to dissemination throughout the brain. Disseminated subclones, however, can differ in genomic and proteomic characteristics to that of the primary tumor, influenced by clonal selection supported by non-genomic factors from each different region of the brain, and lead to distinct survival and proliferative advantages, highlighting the challenge we face in developing treatment strategies that will lead to long-term survival for patients diagnosed with DMG.