Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis

• DOI: 10.1126/science.add5327
• Publication Date: 2023-05-11T17:58:26Z
• Authors: Cassandra Burdziak; Direna Alonso-Cur...; 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
• Keywords: Pancreatic Neoplasms; Mice; Cell Transformation, Neoplastic; Carcinogenesis; Animals; Cell Communication; Pancreas; Article; 3. Good health; Epigenesis, Genetic

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 impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, malignant tissues in autochthonous models pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed diverse, late-emerging neoplastic fates linked these chromatin remodeling at cell-cell communication loci. Using an inference approach, revealed signaling gene modules tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial immune populations was functionally validated mice. Our results uncover neoplasia-specific tissue-remodeling program may be exploited cancer interception.