Wnt缺失与低氧环境调控人类胰腺导管腺癌的鳞状变重编程

Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma

NATURE CELL BIOLOGY

影响因子:19.1

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

DOI: 10.1038/s41556-024-01498-5

摘要

人类胰腺癌的分子多样性包括原生导管样和鳞状细胞样身份，但鳞状细胞转分化的机制尚不清楚。为了全面捕捉人类胰腺癌的分子多样性，我们分析了65个患者来源的胰腺癌类器官系，包括6个腺鳞癌系。H3K27me3媒介的导管谱系特异因子消除和TP63驱动的鳞状细胞程序劫持，驱动了鳞状细胞的定向，在Wnt缺失和低氧条件下提供了生存优势。对正常胰腺导管类器官的基因工程显示，GATA6的丧失和Wnt缺失环境，结合遗传或低氧介导的KDM6A失活，促进了鳞状重编程，从而增强了环境适应性。EZH2抑制剂逆转了表观遗传偏向，抑制了腺鳞癌类器官的生长。我们的研究结果展示了对抗性微环境如何决定人类胰腺癌的分子与组织学演变，为阐释系谱转换的原理与意义提供了新的见解。

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.