研究人员表示，对肿瘤引发的炎症和遗传破坏的反应在形态上没有区别的细胞之间可能有所不同，这表明在早期肿瘤发展过程中，表观遗传可塑性的作用尚未被描述。
为了研究这种可塑性的起源和影响，研究人员对胰腺癌原发模型中的正常、炎症、恶性肿瘤前期和恶性肿瘤组织进行了单细胞分析。研究人员重复性地确定了异质性的细胞状态，这些细胞为不同的、晚期出现的肿瘤命运做好了准备，并将这些状态与细胞-细胞交流位点的染色质重塑联系起来。使用推理方法，研究人员揭示了信号基因模块和组织层面的交流，包括在小鼠中得到功能验证的离散上皮细胞和免疫细胞群之间的肿瘤驱动反馈回路。这些研究结果揭示了一个肿瘤特异性的组织重塑程序，该程序可被用于胰腺癌的拦截。
附：英文原文
Title: Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis
Author: Cassandra Burdziak, Direna Alonso-Curbelo, Thomas Walle, José Reyes, Francisco M. Barriga, Doron Haviv, Yubin Xie, Zhen Zhao, Chujun Julia Zhao, Hsuan-An Chen, Ojasvi Chaudhary, Ignas Masilionis, Zi-Ning Choo, Vianne Gao, Wei Luan, Alexandra Wuest, Yu-Jui Ho, Yuhong Wei, Daniela F. Quail, Richard Koche, Linas Mazutis, Ronan Chaligné, Tal Nawy, Scott W. Lowe, Dana Pe’er
Issue&Volume: 2023-05-12
Abstract: The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci. Using an inference approach, we revealed signaling gene modules and tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that was functionally validated in mice. Our results uncover a neoplasia-specific tissue-remodeling program that may be exploited for pancreatic cancer interception.
DOI: add5327
Source: https://www.science.org/doi/10.1126/science.add5327