Identification of carcinogenesis and tumor progression processes in pancreatic ductal adenocarcinoma using high-throughput proteomics

Abstract

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an overall 5 year-survival rate of just 5%. A better understanding of the carcinogenesis processes and the mechanisms of progression of PDAC is mandatory.Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumor, normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases, were selected for the study. Proteins were extracted from small punches and analyzed by LC-MS/MS using data-independent acquisition. Proteomics data was analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were done using linear mixed models. Three proteomics tumor subtypes were defined. T1 (32% of patients) was related to adhesion, T2 (34%) had metabolic features, and T3 (34%) presented high splicing and nucleoplasm activity. These proteomics subtypes were validated in the PDAC TCGA cohort. Relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. Carcinogenesis in T1 subtype seems to be related to an increase of adhesion and complement activation nodes activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding T2 subtype, it seems that metabolism and, especially, mitochondria act as the motor of cancer development. T3 analyses point out that nucleoplasm, mitochondria and metabolism, and extracellular matrix nodes could be involved in T3 tumors carcinogenesis. Identified processes were different among proteomics subtypes, suggesting that the molecular motor of the disease is different in each subtype. These differences can have implications in the development of future tailored therapeutic approaches for each PDAC proteomics subtype.