Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas

The response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception. One-Sentence Summary Single-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer. ### Competing Interest Statement Scott W. Lowe is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus Inc., PMV Pharmaceuticals, Faeth Therapeutics, and Constellation Pharmaceuticals. A patent application (PTC/US2019/041670, internationally filing date 12 July 2019) has been submitted covering methods for preventing or treating KRAS mutant pancreas cancer with inhibitors of Type 2 cytokine signaling. Direna Alonso-Curbelo and Scott W. Lowe are listed as the inventors. Dana Pe'er is on the scientific advisory board of Insitro.