ArticleNature cell biology2024
Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma.
Article in Nature cell biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Reframing cancer therapy through tumor plasticity.Nature cancer · 2026Review
- Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.Cell stem cell · 2026Article
- Oxygen‑sensing histone demethylase KDM6A modulates chondrocyte‑to‑osteoblast transdifferentiation by activating the Wnt/β‑catenin pathway.International journal of molecular medicine · 2026Article
- Early cellular plasticity promotes progression and dissemination in pancreatic adenocarcinoma.Cancer metastasis reviews · 2026Review
- Translating spatial transcriptomic signatures in adenosquamous carcinoma into bulk prognostic biomarkers in lung adenocarcinoma: a bottom-up approach.NPJ precision oncology · 2026Article
- Advances in liver and pancreas organoids: how far we have come and where we go next.Nature reviews. Gastroenterology & hepatology · 2026Review
- Review
- Drivers of Pancreatic Cancer: Beyond the Big 4.Cancers · 2025Review
- CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma.Cell reports. Medicine · 2025Article
- An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer.Nature cancer · 2025Article
- Article
- Epidemiological characteristics and disease burden of childhood neuroblastoma in Asia: trends and regional differences over the past 30 years.Frontiers in pediatrics · 2025Article
- CircRNA Sequencing Analysis Reveals the Regulatory Role of circ_CDR1as in Penile Squamous Cell Carcinoma via the ceRNA Network.International journal of medical sciences · 2025Article
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Authors and funding
25 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.
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Registered trials
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