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

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.

Functional and Clinical Proteomic Exploration of Pancreatic Cancer

“…performed TMT-based proteomic profiling of 56 PDAC liver metastasis tissues and identified a total of 3960 proteins, from which the profiles of 916 proteins were used to cluster patients into four proteomic subtypes (metabolic, proliferative, progenitor-like, and inflammatory) that were associated with different clinical information, such as risk factors (smoking and drinking), survival time, and responses to drug treatment ( 55 ). A recent study performed DIA-based proteomic profiling of tumor, nontumor, PanIN, and lymph node tissues punched from different regions of FFPE tissues from 52 patients with PDAC ( 56 ). A total of 3927 proteins were identified and 2311 proteins were quantified for hierarchical cluster analysis, which separated tumor samples into three subtypes, with enriched biological processes related to adhesion, metabolic features, and splicing and nucleoplasm activity.…”

Andrographolide induces protective autophagy and targeting DJ-1 triggers reactive oxygen species-induced cell death in pancreatic cancer

“…By 2030, PC is projected to emerge as the second most common cause of cancer-related mortality ( Xie et al, 2022 ). Despite advancements in surgical techniques and chemotherapy for pancreatic ductal adenocarcinoma (PDAC), the 5-year overall survival rate remains dismally low, falling below 7% ( Cascinu et al, 2010 ; Trilla-Fuertes et al, 2022 ). Because PDAC lacks early symptoms, most patients have metastasis.…”