Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment. [Display omitted] •Single-molecule imaging provides a spatial map of repeat and coding RNAs in human PDAC•Interferon response to repeat RNAs perturbs multiple cell types in PDAC tumor•Repeat RNA delivery to stromal cells via extracellular vesicles analogous to a virus•Divergent responses to repeat RNAs between CAFs and PDAC cells are driven by IRF3 Single-molecule spatial imaging in human pancreatic cancers identifies aberrant repeat RNA expression in cancer cells and the surrounding tumor microenvironment linked with alterations in cell fate induced by an interferon response to the viral-like behavior of repeat elements.