日本庆应义塾大学Toshiro Sato等研究人员合作发现，缺乏Wnt信号和低氧环境协同调控人类胰腺导管腺癌的鳞状重编程。这一研究成果于2024年9月4日在线发表在国际学术期刊《自然—细胞生物学》上。

为了全面捕捉人类胰腺癌的分子多样性，研究人员对65种患者来源的胰腺癌类器官谱系进行了分析，其中包括6条腺鳞癌谱系。研究发现，H3K27me3介导的导管谱系决定因子的抹除和TP63驱动的鳞状细胞程序的劫持推动了鳞状细胞的确立，在缺乏Wnt信号和低氧环境中提供了生存优势。

对正常胰腺导管类器官的基因工程研究揭示，GATA6的缺失与Wnt信号缺乏相结合，加上KDM6A的遗传或低氧介导的失活，促进了鳞状重编程，进而增强了环境适应性。EZH2抑制剂能够抵消这种表观遗传偏向，并抑制腺鳞癌类器官的生长。该研究展示了恶劣的微环境如何决定人类胰腺癌的分子和组织学演变，并提供了关于人类癌症谱系转换原理及其重要性的见解。

据介绍，人类胰腺癌以其分子多样性为特征，涵盖了原生导管样和鳞状细胞样特征，但鳞状转分化的机制仍未被充分揭示。

附：英文原文

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

Author: Tamagawa, Hiroki, Fujii, Masayuki, Togasaki, Kazuhiro, Seino, Takashi, Kawasaki, Shintaro, Takano, Ai, Toshimitsu, Kohta, Takahashi, Sirirat, Ohta, Yuki, Matano, Mami, Kawasaki, Kenta, Machida, Yujiro, Sekine, Shigeki, Machinaga, Akihito, Sasai, Ken, Kodama, Yuzo, Kakiuchi, Nobuyuki, Ogawa, Seishi, Hirano, Tomonori, Seno, Hiroshi, Kitago, Minoru, Kitagawa, Yuko, Iwasaki, Eisuke, Kanai, Takanori, Sato, Toshiro

Issue&Volume: 2024-09-04

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. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.

DOI: 10.1038/s41556-024-01498-5

Source: https://www.nature.com/articles/s41556-024-01498-5