WNT缺乏和缺氧环境协调人类胰腺腺癌的鳞状重编程
Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma
影响因子:19.10000
分区:生物学1区 Top / 细胞生物学1区
发表日期:2024 Oct
作者:
Hiroki Tamagawa, Masayuki Fujii, Kazuhiro Togasaki, Takashi Seino, Shintaro Kawasaki, Ai Takano, Kohta Toshimitsu, Sirirat Takahashi, Yuki Ohta, Mami Matano, Kenta Kawasaki, Yujiro Machida, Shigeki Sekine, Akihito Machinaga, Ken Sasai, Yuzo Kodama, Nobuyuki Kakiuchi, Seishi Ogawa, Tomonori Hirano, Hiroshi Seno, Minoru Kitago, Yuko Kitagawa, Eisuke Iwasaki, Takanori Kanai, Toshiro Sato
摘要
人胰腺癌的特征是分子多样性，包括天然管道样和鳞状细胞样的身份，但是鳞状转分化的机制仍然难以捉摸。为了全面捕获人类胰腺癌的分子多样性，我们在这里介绍了65种患者衍生的胰腺癌类器官线，其中包括六种腺泡癌系。 H3K27me3介导的导管谱系指定剂的擦除和TP63驱动的鳞状细胞程序的劫持措施驱动了鳞状细胞的承诺，从而在WNT缺乏的环境和低氧条件下提供了生存益处。正常胰管器官的基因工程表明，GATA6损失和WNT缺陷环境与遗传或缺氧介导的KDM6A失活的一致性，促进了鳞状重编程，从而增强了环境适应性。 EZH2抑制作用平衡了表观遗传偏置，并遏制了腺斑癌器官的生长。我们的结果表明，对抗性的微环境如何决定人类胰腺癌的分子和组织学演化，并为人类癌症谱系转化的原理和意义提供见解。
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.