Researchers publishing in the British Journal of Cancer have developed a dual-oxygen pancreatic cancer organoid system that successfully mirrors the basal and classical molecular subtypes found in human tumors, according to a multi-institutional study led by Kumano, Nakahashi, and Shimomura.
Replicating Tumor Complexity in the Lab
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is difficult to treat because a single tumor can behave like multiple distinct diseases at once.
The Challenge of Tumor Heterogeneity
This biological complexity, known as tumor heterogeneity, means that cancer cells within the same mass can carry different molecular programs, consume different nutrients, interact differently with surrounding tissues, and respond differently to chemotherapy or targeted drugs, according to the study.
Two broad transcriptional identities drive much of this variation: classical tumor cells, which generally retain features of differentiated pancreatic epithelial cells and display gene programs linked to secretory functions, and basal-like cells, which are associated with aggressive clinical outcomes, altered cellular architecture, and enhanced stress responses.
How Dual-Oxygen Environments Reproduce Tumor Diversity
To capture this internal diversity in the laboratory, the research team grew pancreatic cancer organoids—three-dimensional cell cultures that self-organize from tumor tissue while preserving cellular contacts and architecture—under two distinct oxygen environments.
Tumors inside the human body rarely experience uniform oxygen supplies; unevenly distributed blood vessels and rapidly dividing cells create local oxygen gradients, featuring oxygen-rich areas alongside hypoxic zones. By directly manipulating these oxygen levels rather than treating oxygen as a fixed background condition, the investigators observed that the organoids reproduced molecular features corresponding to both basal and classical tumor states, as validated through spatial transcriptomics.
Implications for Personalized Pancreatic Cancer Treatment
The findings indicate that the organoid model does not merely preserve a static genetic identity inherited from a patient tumor sample.
Instead, the dual-oxygen approach demonstrates how environmental contexts, such as oxygen availability, actively shape cellular behavior by influencing transcription factors, mitochondrial respiration, glycolysis, and redox balance. According to the published findings, creating controllable oxygen regimes offers a biologically realistic laboratory model for investigating why pancreatic cancers respond so differently to treatment, paving the way for more reliable testing platforms in personalized medicine.