Investigating transcriptional diversity underlying TRAIL resistance in pancreatic ductal adenocarcinoma through the development of in vitro tumor models

Pancreatic cancer is one of the deadliest solid tumors. Currently, it is the seventh leading cause of cancer death worldwide and the fourth leading cause in the United States. Nevertheless, it is expected to become the second leading cause of cancer death by 2030, due to the significant increase in its incidence in developed countries. Among the different types of pancreatic cancer, PDAC (pancreatic ductal adenocarcinoma) is the most common malignant neoplasm of the exocrine pancreas. One of the most innovative approaches currently being explored in preclinical studies for the treatment of PDAC is the use of a molecule known as Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) which has a potential for inducing apoptosis in cancer cells, while sparing normal cells. However, some types of tumors show intrinsic resistance to TRAIL that remained to be fully characterized. This study investigates TRAIL resistance in PDAC through the development of two distinct in vitro tumor models using the BxPC-3 cell line. The primary objective was to establish TRAIL-resistant cells by exposing them to either a high fixed dose (2000 pg/ml) or escalating (500, 1000, 2000 pg/ml) doses of soluble TRAIL (sTRAIL) over periods ranging from 24 hours to two weeks. The resulting TRAIL-resistant cells were subsequently characterized by RNA sequencing (RNA-seq) to elucidate the mechanisms underlying acquired resistance. Transcriptome profiling revealed the activation of distinct genes and pathways between the high-dose and dose-escalation models, suggesting that cells may employ different strategies to overcome TRAIL-induced apoptosis. These strategies include the upregulation of ribosomal and mRNA translational machinery as well as the attenuation of mitochondrial function and oxidative phosphorylation. However, these findings remain to be fully validated through functional studies.