SOX2 and OCT4 cancer stem cell transcriptional factors mediate radiation and drug resistance in pancreatic tumor organoids.

Abstract

Abstract Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. One of the standard treatments is chemo-radiation therapy that involves gemcitabine or FOLFIRINOX, a combination of leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, combined fractionated radiation therapy (RT). However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) markers OCT-4 and SOX2 in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluotrouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT-4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and 5-FU. The expression of these CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and 5-FU chemotherapy drugs. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT-4 expression, indicating inhibition in CSC self-renewal. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant expression of OCT-4 and SOX2 CSCs markers as compared to normal pancreas, indicating their aberrant regulation in PC and their role in pancreatic cancer. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study highlights the essential role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to further explore the impact of CSCs in PC and identify new therapeutic targets.