IMG-52. Non-invasive hyperpolarized13C imaging of metabolic alterations induced by NF2 loss in meningiomas

Abstract Meningiomas are the most common primary brain tumors in adults. Loss of the tumor suppressor NF2 is the most common genetic alteration in meningiomas and is associated with a higher risk of recurrence. Developing non-invasive imaging biomarkers of NF2 loss can aid in the identification of meningioma patients at higher risk of recurrence. The goal of this study was to determine whether NF2 loss rewires glucose metabolism in preclinical meningioma models and to leverage this information for metabolic imaging of NF2 loss. Using 13C-magnetic resonance spectroscopy (13C-MRS) to quantify [1-13C]-glucose metabolism in isogenic immortalized human meningeal cells that differed only in NF2 expression, we established that NF2 loss shunted glucose-derived pyruvate via glycolysis to lactate as opposed to transamination to alanine or oxidation via the Krebs cycle to glutamate. To confirm the clinical relevance of our findings, we silenced NF2 in patient-derived meningioma cells that endogenously retain NF2 (SF13398) or re-expressed NF2 in patient-derived cells that endogenously lack NF2 (SF12694). Silencing NF2 upregulated [1-13C]-glucose metabolism to lactate in SF13398 cells, while re-expressing NF2 inhibited lactate production in SF12694 cells. Mechanistic studies indicated that NF2 loss upregulated the expression of the glucose transporter SLC2A1, the rate-limiting glycolytic enzyme PGK1, and the lactate exporter SLC16A3. Hyperpolarized 13C-MRS is a clinically applicable MR-based method of imaging the metabolism of hyperpolarized [1-13C]-pyruvate in live cells, animals, and patients. We established that NF2 silencing increased hyperpolarized [1-13C]-pyruvate metabolism to [1-13C]-lactate in SF13398 cells while NF2 re-expression reduced lactate production in SF12694 cells. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to 1-13C]-lactate in vivo was abrogated in mice bearing SF12694 tumors with NF2 re-expression relative to tumors without NF2. Collectively, we demonstrate that NF2 loss drives glycolytic lactate production in meningiomas, an effect that can be visualized by hyperpolarized 13C-MRS in vivo.