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Milan Savani

@milansavani.com

Medical student at UT Southwestern. PhD from the McBrayer Lab at the Children's Research Institute @ UTSW. | nitrogen metabolism in glioma | he/him

Posts Replies Media

Milan Savani @milansavani.com · 29/04/2026

8/12 🎚️ The “switch”: Looking at CAD, the first enzyme in de novo pyrimidine synthesis, we found that uridine deprivation in differentiated cells induced phosphorylation of Ser1900. This site is enriched in primitive tissues and is highly conserved in mammals.

A schema depicting our proposed model: differentiated cells have a "switch" for the de novo pyrimidine synthesis pathway governed by phosphorylation of S1900 on CAD in response to uridine availability. Primitive cells engage this pathway at baseline, regardless of uridine availability.

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Milan Savani @milansavani.com · 29/04/2026

6/12 🐁 In vivo validation: Tracing in xenografted mice and freshly-explanted human glioma and brain tissue revealed that only tumor tissue – not nonmalignant brain – robustly made pyrimidines de novo.

MALDI mass spectrometry imaging data demonstrating tumor-selective enrichment of glutamine labeling, while uridine labels both tumor and nonmalignant brain.

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Milan Savani @milansavani.com · 29/04/2026

5/12 🧫 We checked a panel of differentiated and primitive cells and used induced pluripotent stem cells to validate this finding. The relationship held across models: primitive cells are “builders” (de novo) and differentiated cells are “recyclers” (salvage).

Stable isotope tracing experiments comparing de novo pathway to salvage pathway use in isogenic fibroblasts, neural progenitor cells, and neurons. These data show that fibroblasts and neurons demonstrate a preference for the salvage pathway while neural progenitors engage the de novo pathway.

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Milan Savani @milansavani.com · 29/04/2026

4/12 🧠 Application: Comparing primitive glioma stem-like cells (GSCs) to differentiated astrocytes revealed a fundamental divergence in pyrimidine nucleotide synthesis. While astrocytes predominantly salvage uridine, GSCs also build them from scratch by the de novo pathway.

Sankey diagrams representing increased utilization of de novo pyrimidine synthesis in glioma stem-like cells (GSCs) compared to astrocytes.

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Milan Savani @milansavani.com · 29/04/2026

3/11 🛠️ The platform: We used Human Plasma-like Medium (HPLM, shoutout @jasonrcantor.bsky.social) to generate a library covering amino acids, the urea cycle, nucleic acids, ions, and end products to generate system-level portrait of cellular nitrogen substrate preferences.

Schema describing nitrogen metabolism profiling platform. A media library with individually 15N-labeled metabolites is used for parallel stable istotope tracing assays. After high-resolution LC-MS data acquision, a custom deconvolution algorithm allows for quantification and visualization of rich tracing datasets.

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Milan Savani @milansavani.com · 29/04/2026

1/12 🛣️ Mapping nitrogen metabolism has lagged carbon due to substrate diversity. In @natmetabolism.nature.com, we introduce a platform to do this mapping at scale and identify mechanisms by which differentiation state dictates pyrimidine synthesis. 🧵👇 🔗 www.nature.com/articles/s42...

This celestial scene represents tracking the constellation of metabolites that contribute to cellular nitrogen metabolism. Artwork by Melissa Logies.

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