Fig. 6: MTHFD2 is a potential collateral lethal target across varied genetic backgrounds and microenvironment pressures.
a, UpSet plot of distinguishing and overlapping molecular features (CNA and mutations) of the four ovarian tumour clusters with 19p13.3 deletion identified by NNMF in Fig. 1d. Rows in the overlap matrix represent all combinations of overlaps among four clusters; vertical bar chart represents number of ovarian samples in each cluster; horizontal bar chart represents number of molecular features specific to each row’s overlapping cluster combination; dot plot shows cluster-specific scores of molecular features calculated by NNMF in Fig. 1d. b, Dendrogram estimated from the similarity of molecular features of the four HGSOC clusters with 19p13.3 deletion. c, Multidimensional scaling-based projection of metabolic transcriptional profiles of four HGSOC clusters with 19p13.3 deletion. d, Venn diagram displaying overlap of reactions in reconstructed metabolic models illustrating the distinction between four HGSOC clusters with 19p13.3 deletion. e, Correlation of mRNA expression difference (MTHFD2 versus UQCR11) and dependency scores of MTHFD2 in ovarian cancer lines (Cancer DepMap), estimated using Spearman’s rank correlation test (n = 37). f, TWI and PAUC scores of top-ranking collateral lethal candidate targets in reconstructed metabolic models of clusters 3, 12, 11 and 32. g, Single-cell gene expression of MTHFD2 and UQCR11 from scRNA-seq data from ascitic fluid of patients with ovarian cancer, coloured by cell type (top), average expression of one-carbon metabolic signature no. 1 (middle) and serine, glycine and threonine metabolic signature no. 1 (bottom). Single-cell expression data were normalized using MAGIC and used to estimate Spearman’s correlation coefficient. h, CIBERSORTx-derived, cell-type-specific scores projected on two-dimensional (2D) PHATE embedding of stromal scores representing composition of ovarian tumour samples from TCGA. Joy plots reflect the distribution of cell-specific scores across the quadrants of 2D PHATE embedding. i, Projection of 19p13.3 deletion (log2(CNA < –0.4)) on the 2D PHATE plane representing the stromal composition of ovarian tumour samples from TCGA. j, Average expression of genes in one-carbon metabolic signature no. 1 across the quadrants of stromal 2D PHATE embedding. k, mRNA expression of MTHFD2 and UQCR11 across the quadrants of the stromal 2D PHATE embedding.
