Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells

Abstract

Glioblastomas are highly malignant brain tumors that derive from brain-tumor-initiating cells (BTICs) and can be subdivided into several molecular subtypes. Metformin is an antidiabetic drug currently under investigation as a potential antineoplastic agent. The effects of metformin on glucose metabolism have been extensively studied, but there are only few data on amino acid metabolism. We investigated the basic amino acid profiles of proneural and mesenchymal BTICs to explore a potential distinct utilization and biosynthesis in these subgroups. We further measured extracellular amino acid concentrations of different BTICs at baseline and after treatment with metformin. Effects of metformin on apoptosis and autophagy were determined using Western Blot, annexin V/7-AAD FACS-analyses and a vector containing the human LC3B gene fused to green fluorescent protein. The effects of metformin on BTICs were challenged in an orthotopic BTIC model. The investigated proneural BTICs showed increased activity of the serine and glycine pathway, whereas mesenchymal BTICs in our study preferably metabolized aspartate and glutamate. Metformin treatment led to increased autophagy and strong inhibition of carbon flux from glucose to amino acids in all subtypes. However, oral treatment with metformin at tolerable doses did not significantly inhibit tumor growth in vivo. In conclusion, we found distinct amino acid profiles of proneural and mesenchymal BTICs, and inhibitory effects of metformin on BTICs in vitro. However, further studies are warranted to better understand potential resistance mechanisms against metformin in vivo.

Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma

“…Adeberg et al observed longer progression-free survival among diabetic patients with primary GBM who received metformin treatment [ 59 , 61 ]. Similarly, Seliger et al demonstrated improved overall and progression-free survival in patients with high-grade gliomas, particularly WHO grade III tumors, under metformin therapy [ 62 ]. Notably, this association was more pronounced in grade III gliomas compared to grade IV tumors.…”

“…In a 2019 retrospective report, Seliger et al suggested a potential correlation between metformin treatment and better survival outcomes in patients with grade III gliomas, possibly linked to a higher percentage of IDH mutations in WHO grade III gliomas [ 62 ]. Further analysis by Seliger et al involving a larger cohort of GBM patients failed to establish a significant relationship between metformin monotherapy and overall survival or progression-free survival, underscoring the complexity of the relationship between metformin use and glioma prognosis [ 62 , 63 ].…”