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

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive course and poor prognosis, with most patients succumbing not to the primary tumor burden but rather to systemic spread. While previous research has characterized the molecular subtypes of PDAC and their variable therapeutic vulnerabilities, spatial context within primary and metastatic lesions remained elusive. By employing state-of-the-art spatial transcriptomics on an unprecedented collection of 55 tumor samples from 13 patients, the study maps cellular states and clonal relationships across various metastatic sites, including liver, lung, and peritoneum.

The researchers leveraged rapid autopsy specimens, a resource that permitted a comprehensive survey of both primary tumors and distant metastatic lesions within the same individual. This approach revealed profound shifts in cancer-cell transcriptomic states as tumors disseminate. Notably, distinct lineage states were found to dominate in organ-specific metastases, with the liver and lung harboring markedly different cellular compositions even within the same patient. Such intra-patient heterogeneity underscores the adaptive plasticity of pancreatic cancer cells as they colonize diverse tissue microenvironments.

Crucially, the study constructed phylogenetic trees derived from inferred copy number variations, shedding light on how tumor clones evolve and spread within a single patient. These trees illustrated diverse evolutionary trajectories, highlighting that clonal dissemination is not unidirectional or uniform but rather patient-specific and multifaceted. The ability to map these clonal architectures in spatial context provides essential insights into metastatic seeding patterns and potential vulnerabilities.

Within each metastatic site, multiple tumor lineage states co-existed rather than one dominant clone sweeping through the tissue. Moreover, simultaneous metastatic foci with distinct lineage profiles were observed within the same organ, challenging the traditional view of metastases as monoclonal. This mosaicism reflects both the evolutionary complexity of PDAC and the dynamic interactions between cancer cells and their microenvironment.

The tumor microenvironment (TME) plays a pivotal role in modulating cancer progression and therapy response. By integrating transcriptomic data with spatial information, Pei et al. identified compelling correlations between cancer cell lineage states and features of the surrounding TME. For example, the aggressive basal-like cancer cells predominantly localized with myofibroblastic cancer-associated fibroblasts (myCAFs) expressing transforming growth factor-beta 1 (TGFB1). This spatial proximity was absent in classical or intermediate cancer cell states, indicating a lineage-specific crosstalk that potentially drives more aggressive biology.

Validation via orthogonal methods—including patient-derived organoids and cross-species analysis in mouse models—strengthened these findings, underscoring their biological relevance and reproducibility. Such cross-validation highlights the translational potential of targeting these lineage-specific tumor-stroma interactions in clinical settings.

Interestingly, basal-like cancer cells associated with myCAFs correlated with an exclusion of plasma cells—key components of humoral immunity—from the tumor milieu. Neighboring cell analyses revealed that CXCR4–CXCL12 chemokine signaling pathways may mediate this immune exclusion, unveiling a new axis of immune evasion in metastatic pancreatic cancer. Targeting this signaling axis could reinvigorate immune infiltration and enhance therapeutic efficacy.

The spatially resolved transcriptomic maps also uncover a rich tapestry of cell states and immune contextures, emphasizing the necessity of considering spatial heterogeneity when designing targeted therapies. Tumor lineage plasticity is not merely a snapshot phenomenon but a dynamic process shaped by microenvironmental cues and evolutionary pressures.

By integratively profiling both the genomic and microenvironmental landscapes at high spatial resolution, this study provides a blueprint for understanding how transcriptional plasticity governs metastatic dissemination and immune interactions in PDAC. These insights hold promise for devising novel combination therapies that disrupt key niche interactions and overcome treatment resistance.

The implications of this work extend beyond pancreatic cancer, as spatial transcriptomics can be applied to other refractory metastatic malignancies where lineage heterogeneity and microenvironmental dynamics remain poorly understood. It heralds a new era in cancer research, where spatial context is harnessed to decode tumor complexity and inform precision medicine.

In sum, the meticulous spatial mapping of transcriptomic states across the metastatic spectrum reveals that pancreatic cancer progression is orchestrated by a choreography of tumor cell plasticity, clonal evolution, and niche-specific microenvironmental adaptations. This multidimensional understanding paves the way for innovative therapeutic strategies aimed at dismantling metastatic reservoirs and improving outcomes in this devastating disease.

Subject of Research: Spatial transcriptomic mapping of lineage plasticity and tumor microenvironmental heterogeneity in metastatic pancreatic cancer.

Article Title: Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.

Article References:
Pei, G., Min, J., Rajapakshe, K.I. et al. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature (2025). https://doi.org/10.1038/s41586-025-08927-x

Image Credits: AI Generated