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. 2022 Mar 8;14(6):1378. doi: 10.3390/cancers14061378

Figure 1.

Figure 1

METΔex14 variant-expressing cancers exhibit an enhanced KRAS activation signature. (A) When activated by HGF, the MET receptor is capable of triggering multiple downstream pathways in parallel. This is because its multisubstrate docking domain is capable of recruiting a diverse set of kinases and signaling factors. (B) WB analysis WT MET-amp (H1993) and METΔex14-expressing (Hs746T, H596) cells comparing relative phosphorylation levels of MET effector signaling pathways Ras-MAPK, PI3K-Akt, Stat3, and Src at baseline (0.1% DMSO; 30 min), MET-stimulated (25 ng/mL HGF + 0.1% DMSO; 30 min), or MET-inhibited (25 ng/mL HGF + 10 μM Cabozantinib; 30 min) states. (C) Expression profiling workflow: to identify transcriptomic differences in the molecular profiles of cancer cells addicted to WT MET-amp vs. METΔex14 activity, we performed Gene Set Enrichment Analysis (GSEA) comparing the expression profiles of Hs746T and H596 cells to that of H1993 cells (figure created using BioRender.com). (D) GSEA revealed that gene set expression signatures typically associated with KRAS-driven cancers are among the top-most enriched in METΔex14-expressing cancer lines when compared against the wild type MET cancer line, while gene sets downregulated in KRAS-driven cancers were similarly negatively enriched in METΔex14-expressing cancer lines. As multiple KRAS-related gene sets exist in the “Oncogenic_signatures” MSigDB library curated by UC San Diego and Broad Institute, Fisher’s Exact Test was performed to show significant overrepresentation of KRAS-associated gene sets (bottom right panel). (E) GSEA comparing TCGA RNA-seq data of METΔex14-expressing tumours with WT MET-amp tumours revealed similar enrichment of gene sets associated with KRAS-driven cancers. (F) Gene Set Variation Analysis (GVSA) of TCGA RNA-seq data from (E) showing relative enrichment of KRAS-associated gene sets (compared to all other gene sets in the “Oncogenic_signatures library) for WT MET-amp and in METΔex14-expressing tumours, at single-sample resolution. Heatmap shows positive relative enrichment of KRAS-associated gene sets in METΔex14-expressing lung tumours, and negative relative enrichment in WT MET-amp tumours.