Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). However, ¹⁸F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-¹⁸F-(2S,4R)-fluoroglutamine (¹⁸F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced ¹⁸F-FGln tumor avidity, corresponding with decreased tumor burden. ¹⁸F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where ¹⁸F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that ¹⁸F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.

A subset of childhood posterior fossa ependymomas with poor prognosis is epigenetically similar to H3K27M gliomas.

Significance: MicroRNAs limit gene expression by recruiting a large protein complex known as the RNA-induced silencing complex (RISC) to target mRNAs. While attempting to understand physiological regulation of RISC assembly, we found that most healthy adult tissues retain a reserve of microRNAs not stably associated with target mRNA. Recruitment of microRNAs to large mRNA-containing complexes was accompanied by an increase in their ability to repress targets and was regulated in part by phosphoinositide-3 kinase–RAC-alpha serine/threonine-protein kinase–mechanistic target of rapamycin pathway-dependent enhancement of the glycine-tryptophan protein of 182 kDa protein expression. Data presented here suggest that in vivo, many expressed microRNAs exist in an inactive reserve, allowing resting cells to use microRNAs to dynamically regulate the translation of target mRNAs in their environment.

Cellular proliferation depends on the integration of mitogenic stimuli with environmental conditions. Increasing evidence suggests that microRNAs play a regulatory role in this integration. Here we show that during periods of cellular quiescence, mature microRNAs are stabilized and stored in Argonaute protein complexes that can be activated by mitogenic stimulation to repress mitogen-stimulated targets, thus influencing subsequent cellular responses. In quiescent cells, the majority of microRNAs exist in low molecular weight, Argonaute protein-containing complexes devoid of essential components of the RNA-induced silencing complex (RISC). For at least 3 wk, this pool of Argonaute-associated microRNAs is stable and can be recruited into RISC complexes subsequent to mitogenic stimulation. Using several model systems, we demonstrate that stable Argonaute protein-associated small RNAs are capable of repressing mitogen-induced transcripts. Therefore, mature microRNAs may represent a previously unappreciated form of cellular memory that allows cells to retain posttranscriptional regulatory information over extended periods of cellular quiescence.