Pancreatic cancer has long challenged scientists not only because it is difficult to detect and treat, but also because a single tumour can behave like several different diseases at once. A new study published in the British Journal of Cancer describes an organoid system designed to reproduce one of the most important forms of this internal diversity. The research, led by Kumano, Nakahashi, Shimomura and colleagues, shows that pancreatic cancer organoids grown under two oxygen environments can recapitulate the “basal” and “classical” molecular states observed in human tumours. The findings were validated using spatial transcriptomics, a technology that maps gene activity while preserving information about where individual cells are located within tissue. Together, the results offer a more biologically realistic laboratory model for investigating why pancreatic cancers respond so differently to treatment.
Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is often described as a genetically complex and highly heterogeneous disease. Heterogeneity means that cancer cells within the same tumour may carry different molecular programs, use different nutrients, interact differently with surrounding tissues and respond differently to chemotherapy or targeted drugs. Two broad transcriptional identities have attracted particular attention. Classical tumour cells generally retain features associated with more differentiated pancreatic epithelial cells and can display gene programs linked to secretory or epithelial functions. Basal-like cells, in contrast, are typically associated with a more aggressive state, altered cellular architecture, enhanced stress responses and poorer clinical outcomes. These categories are not rigid boxes; cancer cells can shift between states as their environment changes. Reproducing that flexibility outside the body has been one of the central difficulties in pancreatic cancer research.
Organoids are three-dimensional cell cultures that grow from tumour tissue and self-organise into structures that preserve some features of the original cancer. Unlike conventional two-dimensional cell lines, organoids can maintain cell-to-cell contacts, three-dimensional architecture and, in many cases, a portion of the genetic and phenotypic diversity found in a patient’s tumour. However, organoids are also shaped by the conditions in which they are grown. Oxygen is one of the most influential variables. Tumours are not uniformly supplied with oxygen: blood vessels are unevenly distributed, and rapidly dividing cells can consume oxygen faster than it can be delivered. This creates local oxygen gradients, with relatively oxygen-rich regions existing beside hypoxic zones. Such gradients can alter metabolism, activate stress pathways and influence which genes cancer cells express. The study’s dual-oxygen strategy addresses this environmental factor directly rather than treating oxygen as a fixed background condition.
According to the report, pancreatic cancer organoids exposed to distinct oxygen conditions reproduced molecular features corresponding to both basal and classical tumour states. This observation is important because it suggests that the model does not merely preserve a static genetic identity inherited from the tumour sample. Instead, it can reveal how environmental context helps shape cellular behaviour. Oxygen availability can influence the activity of transcription factors that regulate adaptation to low oxygen, including pathways controlled by hypoxia-inducible factors. It can also affect mitochondrial respiration, glycolysis, redox balance and the production of metabolites that serve as signals inside the cell. These changes may, in turn, remodel gene expression and push tumour cells toward distinct phenotypic programs. By generating organoids under two oxygen regimes, the researchers created a controllable way to examine this interaction between the cancer genome and its surroundings.
The study’s central claim was strengthened through spatial transcriptomics, which provides a type of molecular map rather than a simple list of active genes. In conventional RNA sequencing, tissue is often broken apart before analysis, meaning that information about each cell’s original position is largely lost. Spatial transcriptomics retains the physical coordinates of gene expression, allowing researchers to ask whether particular transcriptional programs are concentrated in specific regions or associated with neighbouring cell populations. This distinction matters in pancreatic cancer, where tumour cells, fibroblasts, immune cells, blood vessels and extracellular matrix form tightly interwoven microenvironments. By comparing the organoid-derived signatures with spatially resolved patterns in tumour tissue, the investigators were able to test whether the basal–classical diversity observed in culture corresponded to structures found in real cancers.
The validation does not mean that an organoid is a complete miniature pancreas or a perfect replica of a patient’s tumour. Organoid cultures generally lack the full immune system, blood circulation, nerve supply and complex stromal architecture present in living tissue. Culture media can also select for particular cell populations, while prolonged propagation may gradually favour clones that grow best under laboratory conditions. These limitations are especially relevant when studying oxygen, because real tumours experience constantly changing gradients rather than two neatly separated experimental environments. Even so, the agreement between the dual-oxygen organoid model and spatial transcriptomic patterns provides evidence that oxygen-sensitive tumour states are not simply artefacts of a dish. It indicates that the model captures at least one biologically meaningful layer of pancreatic cancer organisation.
The implications extend beyond classification. If basal and classical states can be influenced by oxygen and other microenvironmental signals, then treatment resistance may emerge not only from permanent mutations but also from reversible changes in cell identity. A tumour cell that appears relatively differentiated under one condition could adopt a more basal-like, stress-tolerant program under another. Such plasticity may help cancer survive chemotherapy, evade immune attack or repopulate a tumour after treatment. Dual-oxygen organoids could allow researchers to expose matched cancer models to drugs while monitoring whether treatment eliminates a particular state, encourages a transition into another state or leaves behind a resistant population. The system may also support studies of combination therapies designed to target both cancer-cell-intrinsic pathways and the environmental signals that maintain aggressive phenotypes.
The work arrives as cancer researchers increasingly move away from the idea that a tumour can be understood from DNA mutations alone. Genomic alterations remain fundamental, but they operate within a living ecosystem in which oxygen, nutrients, mechanical forces and neighbouring cells continuously shape tumour behaviour. By linking three-dimensional culture, controlled oxygen exposure and spatial transcriptomics, the Japanese research team offers a framework for studying that ecosystem with greater precision. The model could help explain why samples carrying similar mutations develop different clinical courses and why a therapy that works in one region of a tumour may fail in another. Further studies will need to determine how stable the induced states are, how closely they predict patient responses and whether immune or stromal components can be incorporated without losing experimental control. For now, the findings highlight a powerful message: in pancreatic cancer, where a cell grows may be almost as important as the mutations it carries.
Subject of Research: Pancreatic cancer heterogeneity, oxygen-dependent tumour states, cancer organoids and spatial transcriptomics
Article Title: Dual-oxygen pancreatic cancer organoids recapitulate basal–classical heterogeneity validated by spatial transcriptomics
Article References: Kumano, K., Nakahashi, H., Shimomura, O. et al. “Dual-oxygen pancreatic cancer organoids recapitulate basal–classical heterogeneity validated by spatial transcriptomics.” British Journal of Cancer (2026). https://doi.org/10.1038/s41416-026-03577-w
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41416-026-03577-w
Keywords: pancreatic cancer, cancer organoids, tumour heterogeneity, basal-like subtype, classical subtype, oxygen tension, hypoxia, spatial transcriptomics, tumour microenvironment, precision oncology
