Fig. 4: Multi-omics integration identifies key nodes in cachexia-associated metabolic reprogramming under the control of IL6.
Transcriptomic analysis of cachexia target tissues from Ctrl, Non-cax and Cax tumour mice. See also Fig. 1a for the experimental set-up, and Extended Data Fig. 5. n = 4 animals per group. a, Top pathways altered in a similar manner in cachexia target tissues (liver, eWAT, iWAT, heart and GC muscle) from Cax versus Ctrl mice. Data are represented as top z scores: pathways predicted to be activated in red and inhibited in blue (IPA, Qiagen). b, Top pathways commonly altered in both transcriptomics and metabolomics datasets based on P value (IPA, Qiagen) in Cax versus Ctrl mice. Full pathway lists can be found in Supplementary Fig. 2a,b. See also Extended Data Fig. 5h–j for similar analyses in Cax versus Non-cax. c–f, Heatmaps showing the changes in mRNA expression of enzymes involved in one-carbon metabolism and related metabolic pathways (methionine cycle (c), methyltransferases (d), glutathione metabolism (e) and urea cycle (f)). Data from RNA sequencing analysis, presented as log2 fold change (Cax/Ctrl and Cax/Non-cax) and adjusted P values. *P < 0.05. Ahcy, adenosylhomocysteinase; Amd, S-adenosylmethionine decarboxylase; Arg, arginase; Asl, arginosuccinate lyase; Ass, arginosuccinate synthetase; Bhmt, betaine-homocysteine S-methyltransferase; Cbs, cystathionine beta-synthase; Cth, cystathionine gamma-lyase; Dnmt, DNA (cytosine-5)-methyltransferase; Gclc, glutamate-cysteine ligase catalytic subunit; Gnmt, glycine N-methyltransferase; Gpx, glutathione peroxidase; Gss, glutathione synthetase; Gst, glutathione S-transferase; Kmt, lysine (K)-specific methyltransferase; Mat, methionine adenosyltransferase; Mgst, microsomal glutathione S-transferase; Mtap, methylthioadenosine phosphorylase; Mthfr, methylenetetrahydrofolate reductase; Mtr, 5-methyltetrahydrofolate-homocysteine methyltransferase; Mtrr, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase; Nnmt, NAM N-methyltransferase; Odc, ornithine decarboxylase; Otc, ornithine transcarbamylase; Paox, polyamine oxidase; Pemt, phosphatidylethanolamine N-methyltransferase; Prmt, protein arginine N-methyltransferase; Sat, spermidine/spermine N1-acetyltransferase; Shmt, serine hydroxymethyltransferase; Sms, spermine synthase; Srm, spermidine synthase. See also Supplementary Fig. 3 for visual integrations of transcriptomics and metabolomics data in Cax tissues. g, Top potential upstream regulators of observed changes in transcriptomics and metabolomics common to the different metabolic tissues of Cax versus Ctrl mice (IPA, Qiagen). Data are represented as top significant pathways based on P value. h–k, Relative mRNA expression levels of key enzymes (h and i) and metabolites (j and k) of one-carbon metabolism and related pathways in liver (h and j) and GC muscle (i and k) from healthy controls (PBS-injected, grey), C26-control tumour mice (C26-scramble (scr), dark red) and C26-IL6-knock out tumour mice (C26-IL6 KO, orange). Metabolite IDs as in the list presented in Fig. 3b. n = 3 animals per group. Data are the mean ± s.e.m. In h–k, statistical analysis on raw data (2−ΔCt values and MS signal intensities, arbitrary units (AU)) was performed using one-way ANOVA with Tukey’s post-hoc tests or Kruskal–Wallis with Dunn’s post-hoc tests. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
