Identification of Carcinogenesis and Tumor Progression Processes in Pancreatic Ductal Adenocarcinoma Using High-Throughput Proteomics

SIMPLE SUMMARY: Pancreatic cancer is an aggressive disease with a high mortality rate. The study of the biological processes involved in carcinogenesis (tumor formation) and tumor progression (development of metastases) is still necessary. In this work, we established three subtypes of pancreatic tumors according to their protein profiles: one adhesion subtype, a metabolic subtype, and a nucleoplasm subtype. In addition, the identified mechanisms involved in carcinogenesis and in tumor progression differ between subtypes. These differences may need to be considered when designing new treatments. ABSTRACT: Pancreatic 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 the progression of PDAC is mandatory. Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumors, 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 were analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were made using linear mixed models. Three proteomic 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 the T1 subtype seems to be related to an increase of adhesion and complement activation node activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding the 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 tumor carcinogenesis. The 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 for the development of future tailored therapeutic approaches for each PDAC proteomics subtype.