Quantification of Signal Transduction Pathway Activity in Pancreatic Ductal Adenocarcinoma

Patients with pancreatic ductal adenocarcinoma (PDAC) face a very poor prognosis despite advancements in therapeutic strategies. Signal transduction pathways (STPs) that show altered activity in cancer cells may provide new therapeutic targets. Here, we used simultaneous transcriptome-based activation profiling (STAP)-STP technology to identify abnormal STP activity in PDAC. STAP-STP infers STP activity from messenger RNA expression of the target genes of each pathway-associated transcription factor, which is not possible with conventional bioinformatic analysis. We searched the Gene Expression Omnibus database for publicly available PDAC Affymetrix (GPL570) datasets and included six datasets: four datasets with samples from both normal pancreatic duct epithelial cells and PDAC tumor cells and two datasets with PDAC derived cell lines. The activity of the twelve most relevant STPs (androgen receptor, estrogen receptor, PI3K, MAPK, TGFβ, Notch, Hedgehog, Wnt, NFκB, STAT1/2 type I interferon, STAT1/2type II interferon and STAT3) was quantified. Increased activity of the MAPK, STAT3, Wnt, Hedgehog, Notch TGFβ, and NFκB pathways was found in at least two out of four datasets. In PDAC cell lines, MAPK, PI3K, and STAT3 STPs showed higher activity than in patient samples. Cell type deconvolution analysis showed a variable mixture of fibroblasts, immune cells, and tumor cells in the patient samples, which likely influenced the STP activity profile. This is the first time that STP activity has been quantified in PDAC. We conclude that PDAC is characterized by increased MAPK STP activity in combination with high Ki67 and increased activity of developmental pathways (Wnt, Hedgehog, Notch, TGFβ). Drugs targeting specific STPs will be evaluated in PDAC model systems to develop new therapies for PDAC.