Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

Abstract

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

Extracellular 5′-methylthioadenosine inhibits intracellular symmetric dimethylarginine protein methylation of FUSE-binding proteins

“…We suspect that the excretion of MTA is largely a passive event, such that if extracellular MTA is low the MTAP-cell can reduce its intracellular MTA by dilution. This finding is entirely consistent with the recent observation that in MTAP-deleted human glioblastoma tumor tissue there is no increase in MTA (27), raising the idea that the amount of MTAP+ stromal cells may be an important factor when trying to target MTAP-loss therapeutically via PRMT5 inhibition. Smith and colleagues have recently J o u r n a l P r e -p r o o f developed a small molecule PRMT5 inhibitor that specifically targets the PRMT5-MTA complex (28).…”

“…However, our findings and those of Barekatain et al. ( 27 ) suggest that in vivo there may be no elevation in intracellular MTA because of its being metabolized by MTAP+ stromal cells. Additional studies will need to be performed to see how universal is this phenomenon.…”

“…The idea behind this is that such an inhibitor would specifically target MTAP-tumors as their intracellular MTA is elevated. However, our findings and those of Barekatain et al (27) suggest that in vivo there may be no elevation in intracellular MTA due to its being metabolized by MTAP+ stromal cells. Additional studies will need to be performed to see how universal is this phenomena.…”

Glioblastoma and Methionine Addiction

“…In a similar manner, others have considered the potential role of the tumor microenvironment in therapy directed against MTAP-deficient cells [59]. Glioblastoma tumors are heterogenous, containing distinct tumor cell types as well as normal cells including neurons, astrocytes, microglia, macrophages, neutrophils, lymphocytes, and endothelial cells.…”

Physiological Media in Studies of Cell Metabolism

“…At the same time, high MTA concentrations reduce the sensitivity of cells to arginine-N-methyltransferase, which can be used for antitumor therapy. When using the physiological Plasmax medium, Barekatain et al [ 48 ] showed that the above-described mutation does not cause the accumulation of MTA in cells but promotes its secretion. Moreover, secreted MTA can be absorbed by stromal cells in vivo , which has been demonstrated in the co-culture experiment with glioblastoma cells and macrophages.…”