Fig. 3: Safusidenib alters transcriptional patterns in progenitor cells.

a, UMAP plot of snRNA-seq tumor populations only, colored by differentiation potential potency scores calculated using CytoTRACE2 (left). The accompanying density plots illustrate the distribution of potency scores within the progenitor population under pre-safusidenib and post-safusidenib conditions. b, Two-dimensional butterfly plot visualization, with each quadrant corresponding to a tumor cell state: mesenchymal-like (MES-like), neural-progenitor-like (NPC-like), astrocyte-like (AC-like) and oligodendrocyte-progenitor-like (OPC-like) as defined by Neftel et al.⁴³. SC1 and SC2 represent single-cell gene signature scores 1 and 2 also defined by Neftel et al.⁴³. The position of each progenitor nucleus reflects its relative signature scores in the pre-safusidenib and post-safusidenib samples. Cell density is indicated by contour lines. c, Progenitor cell transcriptional program alignment with tumor cell states in responder (positive values) compared with nonresponder (negative values) Spitzer et al.²⁹ samples. d, Ternary plots comparing transcriptional metabolic programs; Krebs (K), lactate (L) and glycolysis (G), in AC-like and OPC-like tumor cells from 11 untreated LGG tumors. e, Quantification of metabolite (α-KG (m/z: 254.08; adducts: M + ACN + Na) and glucose (m/z: 203.05; adducts: M + Na)) intensity score in 100 × 100 µm regions of spatial metabolomics, assigned to AC-like/OPC-like tumor cell ratios calculated by serial spatial transcriptomics sections on samples A–E (example ratio regions annotated, below). Scale bars, 10 μm. Example tumor region with annotated cell type (right, above) and glucose spatial intensity (right, below). Scale bar, 100 μm. f, Quantification of α-KG and glucose in AC-like compared with OPC-like tumor cell states calculated based on spatial transcriptomics annotation relative to spatial metabolomics (Welch t-test). Mean ± s.e.m. Cell type legend as in e. g, Barcode plot of pathways ‘Krebs cycle disorders’ and ‘glutaminolysis and cancer’. Significance calculated via GSEA (n = 9 participants, permutation-based testing). h, Simplified schema of the citric acid cycle and nucleotide synthesis. Blue, increased abundance pre-safusidenib; orange, increased abundance post-safusidenib. UMP, uridine monophosphate; CIT, citrate; OAA, oxaloacetate; MAL, malate; FUM, fumarate; SUC, succinate; ICIT, isocitrate; cis-ACO, cis-aconitate; ND, not detected. Data from LC–MS untargeted analysis (n = 9 participants). i, Ternary plot comparing transcriptional metabolic programs in progenitor cells of K, L and G in responder and nonresponder Spitzer et al.²⁹ samples pre-mIDH inhibitor compared with post-mIDH inhibitor. Inh, inhibitor.