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.

人类胰腺癌的特征是分子多样性，包括天然导管样和鳞状细胞样身份，但鳞状细胞转分化的潜在机制仍然难以捉摸。为了全面捕捉人类胰腺癌的分子多样性，我们在这里分析了 65 个患者来源的胰腺癌类器官系，包括 6 个腺鳞癌系。H3K27me3 介导的导管谱系指示符的擦除和 TP63 驱动的鳞状细胞计划的劫持推动了鳞状细胞定型，在 Wnt 缺陷环境和低氧条件下提供生存益处。正常胰管类器官的基因工程表明，GATA6 缺失和 Wnt 缺陷环境与遗传或缺氧介导的 KDM6A 失活协同，促进鳞状细胞重编程，进而增强环境适应性。EZH2 抑制抵消了表观遗传偏倚并抑制了腺鳞癌类器官的生长。我们的结果展示了对抗性微环境如何决定人类胰腺癌的分子和组织学进化，并为人类癌症谱系转换的原理和意义提供了见解。