# Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response

## TL;DR

This study uses metabolomics and isotope tracing to explore the metabolism of schwannomas and their response to radiation, revealing unique metabolic signatures and resilience to treatment.

## Contribution

The study introduces novel metabolomic and stable isotope tracing approaches to investigate schwannoma biology and radiation response.

## Key findings

- Schwannomas have distinct metabolomic profiles compared to normal Schwann cells.
- Radiation induces minor changes in TCA cycle and nucleotide metabolism in schwannoma xenografts.
- Schwannomas can incorporate glutamine into multiple metabolic pathways even after radiation.

## Abstract

Although schwannomas are common and benign, their growth patterns are often hard to predict. Currently, surgery and radiotherapy are the only standard treatments. Since metabolites are the end products of genes and proteins, metabolomics may reveal downstream tumor features in ways that other -omics cannot. Here, we use metabolomic profiling and stable isotope tracing to characterize primary human schwannomas and describe their changes following radiation in patient-derived xenografts.

Schwannomas collected during surgical resection underwent metabolomic profiling with gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (N = 44) as well as DNA methylation profiling (N = 29). Large tumors were also implanted subcutaneously in athymic mice as patient-derived xenografts. Mice were randomized to radiation treatment or control 4-6 weeks post-implantation. Xenografts were harvested 72 h after radiation for metabolomic profiling (N = 53). Another group of xenografts (N = 33) was injected with U-13C-glutamine prior to tumor harvest for stable isotope tracing.

The schwannoma metabolome differs from that of Schwann cells, and metabolomics-based clustering of schwannomas resembles DNA methylation-based classification. In xenografts, radiation decreases cellular proliferation and produces small but detectable changes to the tricarboxylic acid (TCA) cycle and nucleotide metabolism. 13C-glutamine tracing shows that schwannomas can produce urea cycle intermediates, TCA cycle intermediates, cytosine monophosphate (CMP), and cytosine triphosphate from glutamine even after radiation. CMP was the only metabolite with altered 13C uptake following radiation.

Schwannomas have distinct metabolic signatures compared to the Schwann cells from which they originate. Schwannoma xenograft metabolism is surprisingly robust to radiotherapy, and xenografts readily incorporate glutamine into the TCA cycle, urea cycle, and pyrimidine synthesis.