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

TitleEpigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.
Publication TypeJournal Article
Year of Publication2023
AuthorsBurdziak C, Alonso-Curbelo D, Walle T, Reyes J, Barriga FM, Haviv D, Xie Y, Zhao Z, Zhao CJulia, Chen H-A, Chaudhary O, Masilionis I, Choo Z-N, Gao V, Luan W, Wuest A, Ho Y-J, Wei Y, Quail DF, Koche R, Mazutis L, Chaligne R, Nawy T, Lowe SW, Pe'er D
JournalScience
Volume380
Issue6645
Paginationeadd5327
Date Published2023 May 12
ISSN1095-9203
KeywordsAnimals, Carcinogenesis, Cell Communication, Cell Transformation, Neoplastic, Epigenesis, Genetic, Mice, Pancreas, Pancreatic Neoplasms
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.

DOI10.1126/science.add5327
Alternate JournalScience
PubMed ID37167403
PubMed Central IDPMC10316746
Grant ListU54 CA274492 / CA / NCI NIH HHS / United States
F31 CA246901 / CA / NCI NIH HHS / United States
R25 CA233208 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
DP1 HD084071 / HD / NICHD NIH HHS / United States
U54 CA209975 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States

Person Type: