Mutations-Upstream-of-Metabolomic-Signature Based Functional Analyses Identify Prognostic Biomarkers and Therapeutic Targets in Pancreatic Ductal Adenocarcinoma

Cross-talk among downstream regulatory networks of genome mutations has been the major hypothetical mechanism underlying poor prognosis and low-responsive rates for targeted therapy of pancreatic ductal adenocarcinoma (PDAC). By applying a causal inference-based mutation-upstream-of-the-metabolomic-signature (MUMS), we demonstrated a potential application of prognostic relevant serum metabolomic signature as an indicator to aggregate crosstalk among respective regulatory network downstream of genome mutations, and their collective interference on tumor progression. Moreover, a feature selection of 9-serum metabolites panel also highlights the clinical potential for predicting survival outcomes across multiple PDAC cohorts. Notably, integrating causal inference-based MUMS analysis identified and functional verified GRPEL1 as a novel tumour promoting gene, which shares a common down-stream metabolic signature with mTOR/PI3K/Akt signaling, sensitizing PDAC cells to mTOR inhibition-induced proliferation arrest. Our MUMS based functional cross-talk analysis provided proof-of-concept evidence that serum metabolic signatures reflect crosstalk among tumour mutational landscape, and such co-regulations would provide a novel aspect for identifying neo-targets for targeted therapy and rational based combined therapy design.